In JoVE (1)

Other Publications (157)

Articles by Kathryn J. Wood in JoVE

 JoVE Immunology and Infection

Measurement of T Cell Alloreactivity Using Imaging Flow Cytometry

1Division of Respirology, Departments of Medicine and Immunology, Toronto Lung Transplant Program, Multiorgan Transplant Program, Toronto General Research Institute, University of Toronto and University Health Network, 2Latner Thoracic Surgery Laboratories, Toronto General Research Institute, University Health Network, 3National Institutes of Health Research, Oxford Biomedical Research Centre, Translational Immunology Laboratory, NDORMS, Kennedy Institute of Rheumatology, University of Oxford, 4Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford


JoVE 55283

Other articles by Kathryn J. Wood on PubMed

The Use of Contact Lenses by U.S. Civilian Pilots

Optometry (St. Louis, Mo.). Nov, 2002  |  Pubmed ID: 12516796

Since 1976, the use of contact lenses by civilian pilots has been permitted to correct distant vision for obtaining a Federal Aviation Administration (FAA) aeromedical certificate. This study examined the civil airman population's experience with contact lens use for a 30-year period (1967 to 1997).

Platelet-endothelial Cell Adhesion Molecule-1 (CD31) Expression on Donor Endothelial Cells Attenuates the Development of Transplant Arteriosclerosis

Transplantation. Nov, 2002  |  Pubmed ID: 12451264

Platelet-endothelial cell adhesion molecule(PECAM)-1 (CD31) is expressed on the surface of endothelial cells, platelets, monocytes, neutrophils, and certain T-cell subsets. Treatment of endothelial cells with anti-PECAM-1 antibody inhibits leukocyte transmigration. This study was designed to test the hypothesis that, in transplantation, the absence of PECAM-1 expression on donor endothelial cells would reduce the number of leukocytes transmigrating into the allograft, thereby attenuating the development of transplant arteriosclerosis.

Aviation Accidents and Incidents Associated with the Use of Ophthalmic Devices by Civilian Airmen

Aviation, Space, and Environmental Medicine. Nov, 2002  |  Pubmed ID: 12433236

Approximately 54% of civilian pilots rely on ophthalmic lenses to correct defective vision in order to maintain a valid airman medical certificate. This report reviews aviation accidents and incidents where the use or misuse of ophthalmic devices was considered to have been a contributing factor in the mishap.

Cutting Edge: CD4+CD25+ Alloantigen-specific Immunoregulatory Cells That Can Prevent CD8+ T Cell-mediated Graft Rejection: Implications for Anti-CD154 Immunotherapy

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2002  |  Pubmed ID: 12421913

Blockade of CD40-CD154 interactions can facilitate long-term allograft acceptance in selected rodent and in primate models, but, due to the ability of CD154-independent CD8(+) T cells to initiate graft rejection, this strategy is not always effective. In this work we demonstrate that blockade of the CD40-CD154 pathway at the time of transplantation enables the generation of donor alloantigen-specific CD4(+)CD25(+) regulatory T cells, and that if the regulatory cells are present in sufficient numbers they can suppress allograft rejection mediated by CD154-independent CD8(+) T cells.

Impact of Both Donor and Recipient Strains on Cardiac Allograft Survival After Blockade of the CD40-CD154 Costimulatory Pathway

Transplantation. Sep, 2002  |  Pubmed ID: 12352896

The effectiveness of anti-CD154 monoclonal antibodies in prolonging the survival of mouse allografts is dependent on the strain combination. In this report, we examined the impact of the donor and the recipient strains on the success of CD40-CD154 blockade.

Linked Unresponsiveness: Early Cytokine Gene Expression Profiles in Cardiac Allografts Following Pretreatment of Recipients with Bone Marrow Cells Expressing Donor MHC Alloantigen

Cytokine. Jul, 2002  |  Pubmed ID: 12200107

Linked unresponsiveness operates to induce specific unresponsiveness to fully mismatched vascularized allografts in recipients pretreated with anti-CD4 antibody and syngeneic bone marrow cells expressing a single donor MHC class I alloantigen. The aim of the study was to evaluate early post transplant cytokine expression in allografts where linked unresponsiveness was required for long term graft survival. CBA (H2(k)) mice were pretreated with CBK (H2(k)+K(b)) bone marrow cells under the cover of anti-CD4 antibody 28 days before transplantation of a CBK or a C57BL/10 (H2(b)) cardiac allograft. In both cases graft survival was prolonged (MST=100 days). Intragraft expression for interferon (IFN)-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12(p40), IL-18, iNOS, transforming growth factor (TGF)-beta(1) and C-beta was determined on day 1.5, 3, 7 and 14 after transplantation. Whereas rejecting allografts displayed a sharp peak in IFN-gamma, IL-2, IL-4 and IL-10 expression, non-rejecting allografts were characterized by an initial TGF-beta(1) and IFN-gamma production. An increasing IL-4 expression towards day 14 was a unique feature of linked unresponsiveness. All non-rejecting allografts were characterized by an increasing IL-12(p40) production towards day 14. In summary, the early cytokine expression pattern in allografts after bone marrow induced operational tolerance is influenced by the quantity of donor alloantigens expressed on the graft as well as on the bone marrow inoculum.

Regulatory T Cells in Transplantation

Current Opinion in Immunology. Oct, 2002  |  Pubmed ID: 12183157

There has recently been an explosion of renewed interest in regulatory T cells, particularly those within the CD4(+)CD25(+) population. It is becoming increasingly apparent that these cells exist not only as naturally occurring cells that may contribute to the maintenance of self-tolerance, but they also have the potential to prevent rejection of allografts in experimental models. Such cells have now been identified in humans as well as in rodents.

The Role of the Graft in Establishing Tolerance

Frontiers in Bioscience : a Journal and Virtual Library. May, 2002  |  Pubmed ID: 11991840

At the present time, clinical solid organ transplantation continues to rely on the use of non-specific immunosuppressive protocols in order to prevent graft rejection. However, these regimens bring with them complications related both to the global immunosuppression that they cause, and to toxicity related to individual drugs. The pursuit of protocols that will allow graft-specific tolerance thus remains a major goal of research both in animal models and in clinical practice. There is evidence that the graft itself may play an active part in establishing and maintaining donor-specific hyporesponsiveness and ultimately tolerance; the aim of this review is to analyze this role in more detail.

Kinetics of Transplant Arteriosclerosis in MHC-Class I Mismatched and Fully Allogeneic Mouse Aortic Allografts

Transplantation. Apr, 2002  |  Pubmed ID: 11965033

Transplant arteriosclerosis is still the major complication for long-term allograft survival in clinical transplantation. The aim of our study was to investigate the impact of MHC disparity on the kinetics of the development of transplant arteriosclerosis.

Indirect Allorecognition Can Play an Important Role in the Development of Transplant Arteriosclerosis

Transplantation. Jan, 2002  |  Pubmed ID: 11821744

Indirect allorecognition has been implicated in the initiation of chronic allograft dysfunction. Our aim was to develop an animal model that allowed the contribution of the direct and indirect pathway of allorecognition in the evolution of transplant arteriosclerosis, the main feature of chronic allograft rejection, to be evaluated.

Which Donor Cells Facilitate the Induction of Specific Immunological Unresponsiveness to Alloantigens in Vivo?

Transplantation. Jan, 2002  |  Pubmed ID: 11810055

Alloantigen administration before transplantation, either alone or in combination with therapeutic agents that modulate the functional activity of the responding leukocytes, can be a powerful way of inducing specific unresponsiveness to alloantigens in vivo. In theory, any cell expressing one or more donor alloantigens has the ability to modulate the subsequent immune response to an allograft expressing the same molecules. However, not all sources of cells are equal in their ability to induce specific unresponsiveness. Understanding the molecular mechanisms that influence the way the outcome of the immune response to alloantigen develops, either activation or unresponsiveness to the triggering antigen, will enable the immune system to be manipulated more effectively for therapeutic purposes.

CD25+CD4+ Regulatory T Cells Prevent Graft Rejection: CTLA-4- and IL-10-dependent Immunoregulation of Alloresponses

Journal of Immunology (Baltimore, Md. : 1950). Feb, 2002  |  Pubmed ID: 11801641

Specific and selective immunological unresponsiveness to donor alloantigens can be induced in vivo. We have shown previously that CD25+CD4+ T cells from mice exhibiting long-term operational tolerance to donor alloantigens can regulate rejection of allogeneic skin grafts mediated by CD45RB(high)CD4+ T cells. In this study, we wished to determine whether donor-specific regulatory cells can be generated during the induction phase of unresponsiveness, i.e., before transplantation. We provide evidence that pretreatment with anti-CD4 Ab plus a donor-specific transfusion generates donor-specific regulatory CD25+CD4+ T cells that can suppress rejection of skin grafts mediated by naive CD45RB(high)CD4+ T cells. Regulatory cells were contained only in the CD25+ fraction, as equivalent numbers of CD25-CD4+ T cells were unable to regulate rejection. This pretreatment strategy led to increased expression of CD122 by the CD25+CD4+ T cells. Blockade of both the IL-10 and CTLA-4 pathways abrogated immunoregulation mediated by CD25+ T cells, suggesting that IL-10 and CTLA-4 are required for the functional activity of this population of immunoregulatory T cells. In clinical transplantation, the generation of regulatory T cells that could provide dynamic control of rejection responses is a possible route to permanent graft survival without the need for long-term immunosuppression.

Regulatory Cells in Transplantation

Novartis Foundation Symposium. 2003  |  Pubmed ID: 14609219

Regulatory T cells can play an important role in both the induction and maintenance of tolerance to donor alloantigens in vivo. Regulatory activity specific for donor alloantingens is enriched amongst CD4+CD25+ T cells in some settings and can be induced by manipulating the immune system before transplantation. Donor alloantigen-specific CD4+CD25+ regulatory T cells can control aggressive CD4+ as well as CD8+ T cells thereby preventing rejection and can mediate linked unresponsiveness. In vivo, donor alloantigen specific CD4+CD25+ cells are dependent on interleukin (IL)10 and CTLA4 for functional activity. These populations of regulatory cells induced by manipulating the adult immune system therefore have properties in common with naturally occurring regulatory T cells. The active regulation/suppression of immune responsiveness to donor alloantigens offers a way to silence aggressive immune responses directed to donor alloantigens thereby preventing damage to the graft from being inflicted. The generation of regulatory T cells with defined alloantigen specificity could provide dynamic control of rejection responses and offers a potential route to permanent graft survival without the need for life-long non-specific immunosuppression.

Increased Expression of Transforming Growth Factor-beta and Eosinophil Infiltration is Associated with the Development of Transplant Arteriosclerosis in Long-term Surviving Cardiac Allografts

Transplantation. Oct, 2003  |  Pubmed ID: 14557761

Transplant arteriosclerosis is a major limiting factor for long-term function of allografts in clinical transplantation. This study investigated the impact of three different protocols capable of inducing long-term allograft survival on the development of transplant arteriosclerosis and immune response in cardiac allografts.

Pretransplant Blood Transfusion Without Additional Immunotherapy Generates CD25+CD4+ Regulatory T Cells: a Potential Explanation for the Blood-transfusion Effect

Transplantation. Aug, 2003  |  Pubmed ID: 12923427

Preoperative blood transfusion has had a significant historic impact on graft outcome in clinical kidney transplantation, and the effect has been widely replicated in many experimental transplant models. Although the mechanisms underlying the blood-transfusion effect are poorly understood, one possibility is that preexposure to alloantigen results in the induction of regulatory cells with the capacity to control the effector arm of the immune response.

Impact of Hepatic Rearterialization on Reperfusion Injury and Outcome After Mouse Liver Transplantation

Transplantation. Jul, 2003  |  Pubmed ID: 12883187

Nonarterialized mouse liver transplantation is a well-established model for immunologic studies on rejection and tolerance mechanisms. However, the importance of graft arterialization has-in contrast to rat liver transplantation-not been thoroughly examined in the mouse model. The aim of the current study was to investigate the impact of arterial reconstruction on long-term graft survival, histologic alterations, ischemic liver damage, and early immunologic activation pathways.

Passenger Leukocytes and Microchimerism: What Role in Tolerance Induction?

Transplantation. May, 2003  |  Pubmed ID: 12819485

The role of passenger leukocytes in determining the outcome after transplantation is complex. In some settings, donor-derived passenger leukocytes can initiate graft rejection, whereas in others they contribute to graft acceptance. Both donor and recipient factors contribute to this potential dual role. Understanding the interaction between passenger leukocytes and the recipient's immune system, particularly after liver transplantation, may provide important clues for developing novel strategies for inducing specific unresponsiveness to donor alloantigens.

Mouse Endothelial CD40 Expression Does Not Play a Role During the Development of Transplant Arteriosclerosis

Endothelium : Journal of Endothelial Cell Research. 2003  |  Pubmed ID: 12791519

Endothelial cells (ECs) are of major interest in allograft rejection. The authors and others have recently shown in different mouse allograft models that, during the development of transplant arteriosclerosis, donor ECs are replaced by recipient ECs. It was the aim of this study to characterize the phenotype of ECs during the development of transplant arteriosclerosis further, with particular interest in their capability to express CD40. Abdominal aortic allografts were transplanted across a full major histocompatibility complex (MHC) barrier using BALB/c (H-2d) mice as donors and C57BL/6 (H-2b) mice as transplant recipients. Aortic allografts were harvested on days 7 and 30 after transplantation and analyzed by double-immunohistochemistry for expression of CD40 and CD31. As the authors have previously shown that ECs in the aortic allograft model are of donor origin on day 7 after transplantation, whereas by day 30 donor ECs have been replaced by ECs of recipient origin, these two time points were chosen for analysis of CD40 expression. Double-immunohistochemistry for CD40 and CD31 revealed no endothelial expression of CD40 at either time point. These initial results obtained with the anti-CD40 monoclonal antibody (mAb) (clone 3/23) were confirmed by two further experiments using two different anti-CD40 mAbs (clone HM40-3 and clone 1/10) that bind to epitopes of the CD40 receptor distinct to that of 3/23. Neither mAb revealed endothelial expression of CD40. Further analysis of the composition of the cellular infiltrate demonstrated that the majority of macrophages were CD40 positive. The data indicate that in this mouse model of aortic transplantation, neither recipient- nor donor-derived ECs express CD40 during the development of transplant arteriosclerosis. Therefore, in contrast to rat or human ECs, CD40 expression by mouse ECs does not seem to play a major role in this form of allograft rejection.

In Vivo Models of Inflammation: Immune Rejection and Skin Transplantation in Vivo

Methods in Molecular Biology (Clifton, N.J.). 2003  |  Pubmed ID: 12769492

Retroviral Transfer of Donor MHC Class I or MHC Class II Genes into Recipient Bone Marrow Cells Can Induce Operational Tolerance to Alloantigens in Vivo

Human Gene Therapy. Apr, 2003  |  Pubmed ID: 12718767

Infusion of allogeneic, donor bone marrow (BM) can induce specific immunological unresponsiveness in vivo resulting in long-term acceptance of subsequent fully allogeneic, donor-type solid organ grafts, but this may be associated with graft-versus-host disease. We hypothesize that transfer of donor MHC gene(s) to recipient-type BM or hematopoietic stem cells would enable delivery of donor alloantigens to the recipient without the risk of graft-versus-host disease. This strategy could also potentially take advantage of linked suppression to induce specific unresponsiveness to additional alloantigens expressed by the solid organ graft. We found that infusion of 5 x 10(6) CBA (H-2(k)) recipient mouse BM cells transduced with a recombinant replication-defective retrovirus encoding either a single donor MHC class I or class II gene (H-2K(b) or H-2IA(b)) in combination with anti-CD4 monoclonal antibody resulted in long-term survival of C57BL/10 (H-2(b)) but not third-party NZW (H-2(z)) heart grafts. BM cells (3 x 10(3)) enriched for hematopoietic stem cells by sorting for c-Kit(+), lineage-negative cells, were able to induce long-term allograft survival in 50% of recipients after transduction with the vector encoding a single donor MHC class I gene. These results have important implications for future strategies to enhance clinical allograft survival by delivery of donor alloantigens.

Regulatory T Cells in Transplantation Tolerance

Nature Reviews. Immunology. Mar, 2003  |  Pubmed ID: 12658268

The identification and characterization of regulatory T (T(Reg)) cells that can control immune responsiveness to alloantigens have opened up exciting opportunities for new therapies in transplantation. After exposure to alloantigens in vivo, alloantigen-specific immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25. In vivo, common mechanisms seem to underpin the activity of CD4+CD25+ T(Reg) cells in both naive and manipulated hosts. However, the origin, allorecognition properties and molecular basis for the suppressive activity of CD4+CD25+ T(Reg) cells, as well as their relationship to other populations of regulatory cells that exist after transplantation, remain a matter of debate..

Syngeneic Bone Marrow Transduced with a Recombinant Retroviral Vector to Express Endoplasmic Reticulum Signal-sequence-deleted Major Histocompatibility Complex Class-I Alloantigen Can Induce Specific Immunologic Unresponsiveness in Vivo

Transplantation. Feb, 2003  |  Pubmed ID: 12605123

Long-term survival of fully allogeneic cardiac grafts can be induced in mice through transduction of recipient bone marrow cells (BMCs) with a recombinant retroviral vector encoding a single full-length major histocompatibility complex (MHC) class I alloantigen. This study investigated whether cell surface expression of the transduced MHC antigen was necessary for the induction of specific unresponsiveness. METHOD The signal sequence for translocation into the endoplasmic reticulum was deleted from H-2K (SDELKb). Syngeneic BMCs from CBA.Ca (H2k) recipients were transduced with an MFG retroviral vector encoding either wild-type Kb or the mutant SDELKb and reinfused in conjunction with an anti-CD4 therapy. Four weeks later, the recipients underwent transplantation with a fully allogeneic C57BL/10 cardiac graft. Graft survival and the development of transplant arteriosclerosis were assessed.

Analyses of Peripheral Blood Mononuclear Cells in Operational Tolerance After Pediatric Living Donor Liver Transplantation

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Dec, 2004  |  Pubmed ID: 15575917

Operational tolerance (graft acceptance in an immunosuppression (IS)-free environment) after living-donor liver transplantation (LDLT) could occur by our elective protocol in some patients. There is, nevertheless, no reliable parameter to monitor patients who may discontinue IS without a risk of rejection. To identify such parameters, we systemically phenotyped peripheral blood mononuclear cells from operationally tolerant patients. An increase was observed in the frequency of CD4+CD25high+ cells, B cells and Vdelta1/Vdelta2 gammadeltaT-cells ratio in operationally tolerant patients (Gr-tol; n = 12), compared with those from age-matched volunteers (Gr-vol; n = 24) or patients on IS (Gr-IS; n = 19). The frequency of NK cells was decreased in Gr-tol, compared with those in Gr-IS or Gr-vol. The frequency of NKT cells was decreased after LDLT, compared with that in Gr-vol. Although the contribution of those subsets to the tolerant state remains elusive, the results may provide important clues for reliable indicators of tolerance after LDLT.

Changing Demographics and Vision Restrictions in Civilian Pilots and Their Clinical Implications

Aviation, Space, and Environmental Medicine. Sep, 2004  |  Pubmed ID: 15460630

The Federal Aviation Administration guides policy decisions through the study of medical pathologies and visual disorders common to aviators. The purpose of this study is to examine demographic statistics present in the civil airman population, including vision restrictions, and their relevance to the clinical care of aviators.

Transplantation Tolerance by Donor MHC Gene Transfer

Current Gene Therapy. Sep, 2004  |  Pubmed ID: 15384946

Replacing the function of diseased organs by transplantation has proved to be highly successful in the past four decades. The immune system poses the most significant barrier to the long term survival of the transplanted organs. Without lifelong treatment with powerful immunosuppressive agents to keep the immune response at bay, organ grafts will invariably be rejected. However, current immunosuppressive agents are non-specific and leave transplant recipients more susceptible to opportunistic infections and tumour development. Achieving donor specific tolerance would eliminate the need for lifelong treatment with these agents and thereby, avoid the associated side effects. There have been many exciting new developments in immunopharmacology and in the understanding of the mechanisms of rejection and tolerance. These developments on their own, or in combination with the use of gene therapy techniques may allow the induction of transplantation tolerance in human recipients of allografts in the future. Pretransplant exposure to donor MHC antigens has been highly successful strategy for tolerance induction in experimental models. Pretransplant blood transfusion, and more recently administration of donor bone marrow, has been used in an attempt to prolong graft survival in human. However, using fully allogeneic donor bone marrow carries the risk of graft versus host disease. Gene therapy may allow this approach to be used without this risk. Here, we review efforts to induce transplantation tolerance by gene transfer of donor MHC genes to recipient derived cells and show that this may be a potential strategy to achieve the holy grail of organ transplantation: donor specific tolerance.

Natural Sunlight and Its Association to Civil Aviation Accidents

Optometry (St. Louis, Mo.). Aug, 2004  |  Pubmed ID: 15372789

Glare is a temporary visual sensation produced by luminance within the visual field that is significantly greater than that to which the eyes are adapted. Glare from natural and artificial light sources can result in temporary visual impairment, increasing the risk of an accident. This study investigates the relationship between visual impairment from natural sunlight and aviation accidents.

Intrathymic Delivery of Plasmid-encoding Endoplasmic Reticulum Signal-sequence-deleted MHC Class I Alloantigen Can Induce Long-term Allograft Survival

Transplant International : Official Journal of the European Society for Organ Transplantation. Sep, 2004  |  Pubmed ID: 15372145

Intrathymic (IT) delivery of donor alloantigen is a potent strategy to induce operational tolerance. In this study we determined whether this effect was dependent on direct allorecognition of the tolerogen. Ten microgrammes of plasmid, encoding either the wildtype major histocompatibility complex (MHC) class I molecule K(b) or a truncated form in which the signal sequence for translocation into the endoplasmic reticulum was deleted, preventing cell surface expression and direct allorecognition of the tolerogen, was administered intrathymically to CBA.Ca (H2(k)) recipients. In addition, recipients were treated with anti-CD4 antibody (YTA3.1) at the time of IT injection and underwent transplantation 28 days later with a fully mismatched C57BL/10 (H2(b)) cardiac allograft. Wildtype, as well as truncated K(b) genes, were able to induce long-term survival of the cardiac allografts, in contrast to empty control plasmid. Reverse-transcriptase PCR showed expression of the K(b) genes for up to 28 days in thymus and spleen of pretreated recipients. These data show that direct allorecognition of the tolerogen was not required for the induction of long-term allograft survival following the introduction of plasmid-encoded MHC alloantigen into the thymus.

Dependency of Direct Pathway CD4+ T Cells on CD40-CD154 Costimulation is Determined by Nature and Microenvironment of Primary Contact with Alloantigen

Journal of Immunology (Baltimore, Md. : 1950). Feb, 2004  |  Pubmed ID: 14764682

Blockade of the CD40-CD154 costimulatory pathway can inhibit CD4(+) T cell-mediated alloimmune responses. The aim of this study was to define the in vivo requirement for CD40-CD154 costimulation by CD4(+) T cells that respond to alloantigen following direct recognition. We used TCR-transgenic CD4(+) T cells that are reactive to the MHC class II alloantigen, H2A(s). An experimental in vivo model was established that allowed direct comparison of the fate of a trace population of H2A(s)-reactive CD4(+) T cells when challenged with different forms of H2A(s+) alloantigen under conditions of CD40-CD154 costimulation blockade. In this study, we demonstrate that an i.v. infusion of H2A(s+) leukocytes in combination with anti-CD154 therapy rapidly deletes H2A(s)-reactive CD4(+) T cells. In contrast, following transplantation of an H2A(s+) cardiac allograft, H2A(s)-reactive CD4(+) T cell responses were unaffected by blocking CD40-CD154 interactions. Consistent with these findings, combined treatment with donor leukocytes and anti-CD154 therapy was found to be more effective in prolonging the survival of cardiac allografts compared with CD154 mAb treatment alone. The dominant mechanism by which donor leukocyte infusion and anti-CD154 therapy facilitate allograft acceptance is deletion of donor-reactive direct pathway T cells. No evidence for the generation of regulatory cells by this combined therapy was found. Taken together, these results clearly demonstrate that naive alloreactive CD4(+) T cells have distinct requirements for CD40-CD154 costimulation depending on the form and microenvironment of primary alloantigen contact.

Regulatory T Cells: Potential in Organ Transplantation

Transplantation. Jan, 2004  |  Pubmed ID: 14726760

Active regulation or suppression of donor reactive cells is emerging as a key mechanism for inducing and maintaining unresponsiveness to donor alloantigens. Accumulating evidence suggests that a balance between immunoregulation and deletion of donor alloantigen reactive T cells can provide effective control of immune responsiveness after organ or cell transplantation. In many settings, immunoregulatory activity is enriched in CD4+ T cells that express high levels of CD25, and common mechanisms appear to be responsible for the activity of regulatory T cells in both transplantation and the control of reactivity to self-antigens.

Alloantigen-induced CD25+CD4+ Regulatory T Cells Can Develop in Vivo from CD25-CD4+ Precursors in a Thymus-independent Process

Journal of Immunology (Baltimore, Md. : 1950). Jan, 2004  |  Pubmed ID: 14707064

The capacity of naturally occurring autoreactive CD25+CD4+ regulatory T cells (Treg) to control immune responses both in vivo and in vitro is now well established. It has been demonstrated that these cells undergo positive selection within the thymus and appear to enter the periphery as committed CD25+CD4+ Treg. We have shown previously that CD25+CD4+ Treg with the capacity to prevent skin allograft rejection can be generated by pretreatment with donor alloantigen under the cover of anti-CD4 therapy. Here we demonstrate that this process does not require an intact thymus. Furthermore, generation of these Treg is not dependent on the expansion of CD25+CD4+ thymic emigrants, because depletion of CD25+ cells before pretreatment does not prevent Treg development, and Treg can be generated from CD25-CD4+ precursors. Taken together, these results clearly demonstrate that CD25+CD4+ Treg can be generated in the periphery from CD25-CD4+ precursors in a pathway distinct to that by which naturally occurring autoreactive CD25+CD4+ Treg develop. These observations may have important implications for the design of protocols, both experimental and clinical, for the induction of tolerance to autoantigens or alloantigens in adults with limited thymic function.

The Needs for a Global Alliance for Transplantation

Clinical Transplants. 2005  |  Pubmed ID: 17424746

The Relevance of Adhesion Molecules in the Classification of Squamous Cell Carcinoma of the Head and Neck

Anticancer Research. Nov-Dec, 2005  |  Pubmed ID: 16309209

Clinical studies have demonstrated increased serum levels of E-selectin, P-selectin and VCAM-1 in patients with squamous cell carcinomas, which correlate with expression in the primary tumour. For this reason, selectin expression may also support the diagnosis and be of prognostic value in squamous cell carcinoma of the head and neck (SCCHN).

Transplanting Stem Cells: Potential Targets for Immune Attack. Modulating the Immune Response Against Embryonic Stem Cell Transplantation

Advanced Drug Delivery Reviews. Dec, 2005  |  Pubmed ID: 16289432

The curative promise of stem cells and their descendants for tissue regeneration and repair is currently the subject of an intense research effort worldwide. If it proves feasible to differentiate stem cells into specific tissues reliably and safely, this approach will be invaluable in the treatment of diseases that lead to organ degeneration or failure, providing an alternative or supplementary source of tissue for transplantation. Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of a pre-implantation blastocyst that can produce all cells and tissues of the foetus. In recent years, several laboratories have described the directed differentiation of ES cells into multiple mature cell types including: cardiomyocytes; haemopoietic cells; hepatocytes; neurones; muscle cells and both endocrine and exocrine cells of the pancreas. How the immune system of the host will respond when these ES cell-derived mature cells are transplanted is ill defined. This review will focus on the potential mechanisms that the immune system could use to target ES cell-derived transplants and how unwanted responses might be prevented.

Inhibition of Chronic Rejection and Development of Tolerogenic T Cells After ICOS-ICOSL and CD40-CD40L Co-stimulation Blockade

Transplantation. Jul, 2005  |  Pubmed ID: 16041271

Chemokine Gene Expression During Allograft Rejection: Comparison of Two Quantitative PCR Techniques

Journal of Immunological Methods. Jun, 2005  |  Pubmed ID: 16018884

The ability to analyse expression of genes rapidly in small samples of tissue is essential for the clinical assessment of many conditions, including the onset of rejection after transplantation. Chemokines have been shown to play a critical role in leukocyte recruitment to transplanted organs and in leukocyte localisation within tissues and antagonism of certain chemokines or chemokine receptors, identified as being up-regulated during allograft rejection, it has been shown to delay leukocyte infiltration into the graft and to prolong graft survival. The analysis of chemokine and chemokine receptor expression in allografts after transplantation may therefore be a useful early indicator of the onset of rejection. RT-PCR techniques are the most sensitive for the detection of low abundance mRNA when the amount of tissue sample is limited. Here we compared competitive-quantitative RT-PCR (CQ-PCR) with real-time PCR for the sequential quantification of chemokine transcripts after transplantation of a fully MHC mismatched mouse cardiac allograft. Although CQ-PCR was found to be an accurate and sensitive technique, real-time PCR was more sensitive and reproducible. Despite the reproducibility, differences in sensitivity between the two techniques were high. Real-time PCR avoids hazardous post-PCR manipulations thereby decreasing the potential risk of sample contamination, and offers the advantage that several genes can be analysed from small tissue samples in a shorter period of time, a key parameter for graft biopsy samples. Real-time PCR was therefore used to extend the analysis of intragraft mRNA chemokine expression levels. Expression of CXCL5 and CCL2 was found to be independent of T cell infiltration while intragraft expression of CCL3, CCL4, CCL5, CXCL9, CXCL10, XCL1 and CCL1 was clearly T cell dependent and increased significantly with time after transplantation. Overall, real-time PCR analysis showed that chemokine gene expression during rejection is clearly distinct from that in non-rejecting syngeneic grafts and is altered by the onset of infiltration of alloantigen-reactive T cells into the graft.

Induction of Transplantation Tolerance-the Potential of Regulatory T Cells

Transplant Immunology. Aug, 2005  |  Pubmed ID: 15982567

Solid organ transplantation is widely accepted as an effective treatment for end organ failure. Although the treatment with immunosuppressive drugs has undoubtedly greatly improved graft survival, chronic rejection still has considerable impact on long term outcome. This, together with the undesirable side effects associated with life long treatment with immunosuppressive drugs, have significant implications for long term outcomes. In a small number of patients, drug non-compliance as well as controlled reduction or removal of maintenance immune suppressive drug therapy has led to the uncovering of a tolerant state. The challenge of achieving improved monitoring of all transplant patients may allow tailoring of immunosupression in a proportion of recipients thereby increasing the opportunities for the induction of specific unresponsiveness to donor alloantigens in the future. The immune system using several mechanisms to both induce and maintain tolerance to alloantigens, including the deletion of allo-reactive T cells, the induction of anergy, clonal exhaustion, ignorance and active suppression (immunoregulation) of allo-responses. A minor subpopulation of CD4+ T cells, regulatory or suppressor CD4+ T cells that co-express the cell-surface molecule CD25 (IL2 alpha subunit) at a high level may play a major role in the maintenance of specific unresponsiveness and operational tolerance to donor antigens in vivo. Intensive investigation of these cells in recent years has started to uncover the mechanisms of active suppression by regulatory T cells in this setting.

IFN-gamma Production by Alloantigen-reactive Regulatory T Cells is Important for Their Regulatory Function in Vivo

The Journal of Experimental Medicine. Jun, 2005  |  Pubmed ID: 15967822

The significance of cytokine production by CD4(+) regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RB(high)CD4(+) T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25(+)CD4(+) T cells, but not CD25(-)CD4(+) T cells, showed a fivefold increase in IFN-gamma mRNA expression within 24 h of re-encountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-gamma at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RB(high)CD4(+) effector T cells into Rag(-/-) skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-gamma-deficient mice. These data support a unique role for IFN-gamma in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo.

CD25+CD4+ Regulatory T Cells Generated by Exposure to a Model Protein Antigen Prevent Allograft Rejection: Antigen-specific Reactivation in Vivo is Critical for Bystander Regulation

Blood. Jun, 2005  |  Pubmed ID: 15713793

The importance of CD25(+)CD4(+) regulatory T (Treg) cells in the control of immune responses is established, but their antigen specificity in vivo remains unclear. Understanding Treg-cell specificity requirements will be important if their potential is to be developed for immunotherapy. Pretreatment of recipient mice with donor alloantigen plus anti-CD4 antibody generates CD25(+)CD4(+) Treg cells with the capacity to prevent skin allograft rejection in adoptive transfer recipients. Here we demonstrate that, although this regulation can be antigen-specific, reactivation with the original tolerizing alloantigen allows the Treg cells to suppress rejection of third-party allografts. Aware of the limitations of alloantigen pretreatment, we asked whether graft-protective Treg cells could be generated against unrelated, nongraft antigens. We demonstrate that bystander regulation also extends to CD25(+)CD4(+) Treg cells generated in vivo by exposure to nominal antigens under anti-CD4 antibody cover. Providing these Treg cells are reexposed to the tolerizing antigens before adoptive transfer, they prevent the rejection of fully allogeneic skin grafts. That this might form the basis of a clinically relevant tolerance induction strategy is demonstrated by the fact that, when combined with subtherapeutic anti-CD8 antibody, Treg cells generated in response to nongraft antigens facilitate the acceptance of cardiac allografts in primary recipients.

Is B Cell Tolerance Essential for Transplantation Tolerance?

Transplantation. Feb, 2005  |  Pubmed ID: 15699748

In some transplantation settings, achieving B cell as well as T cell tolerance will be essential in order to ensure long-term graft survival. However, in other situations, although B cell tolerance could potentially offer advantages to the long-term function of the graft and may therefore be desirable, there is no evidence that inducing B cell tolerance alongside T cell tolerance is essential. This overview forms part of a debate discussing the potential role of B cell tolerance in transplantation and uses selected examples in the literature to address the question: is B cell tolerance essential for transplantation tolerance?

The Transplantation Society: Building on Success

Transplantation. Dec, 2006  |  Pubmed ID: 17198234

Recipient Memory-like Lymphocytes Remain Unresponsive to Graft Antigens After CAMPATH-1H Induction with Reduced Maintenance Immunosuppression

Transplantation. Nov, 2006  |  Pubmed ID: 17130784

Treatment with CAMPATH-1H at the time of transplantation allows reduced maintenance immunosuppression. We hypothesized that CAMPATH-1H induction would modulate the response of repopulating leukocytes to donor alloantigens.

CD25+CD4+ Regulatory T Cells Develop in Mice Not Only During Spontaneous Acceptance of Liver Allografts but Also After Acute Allograft Rejection

Transplantation. Nov, 2006  |  Pubmed ID: 17102772

Liver grafts transplanted across a major histocompatibility barrier are accepted spontaneously and induce donor specific tolerance in some species. Here, we investigated whether liver allograft acceptance is characterized by, and depends upon, the presence of donor reactive CD25CD4 regulatory T cells.

The Impact of Memory T Cells on Rejection and the Induction of Tolerance

Transplantation. Jul, 2006  |  Pubmed ID: 16861933

Accumulating evidence suggests that alloreactive memory T cells (Tm) may be generated in transplant recipients that have not previously been exposed to alloantigen through mechanisms such as cross-reactivity and homeostatic proliferation. The presence of Tm correlates with both acute and chronic rejection episodes and, furthermore, may be responsible for the failure to induce tolerance in large animal and clinical settings. A clearer understanding of how Tm function and their requirements to mount an effective response to alloantigen will be key to further attempts to translate tolerance induction protocols from the experimental setting to the clinic.

Interferon Gamma: a Crucial Role in the Function of Induced Regulatory T Cells in Vivo

Trends in Immunology. Apr, 2006  |  Pubmed ID: 16527542

Interferon (IFN)gamma can have paradoxical functions, eliciting inflammatory T helper 1 (Th1)-driven immune responses in some circumstances, and enabling induced regulatory T (Treg) cells to control immune responses in others. Here, we propose a model in which IFNgamma produced rapidly and only transiently by induced Treg cells is crucial to their function in vivo. This early production of IFNgamma by induced Treg cells during an immune response can directly inhibit the activation and proliferation of IFNgammaR1- and IFNgammaR2-bearing T cells. Furthermore, it can indirectly prevent further T-cell activation by creating a microenvironment that influences the function of antigen-presenting cells (APCs) as a result of IFNgamma-induced inducible nitric oxide synthase (iNOS), indoleamine-2,3-dioxygenase (IDO) and heme oxygenase (HO)-1 expression.

Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help

Journal of Immunology (Baltimore, Md. : 1950). Feb, 2006  |  Pubmed ID: 16455988

There is now considerable evidence suggesting that CD8(+) T cells are able to generate effector but not functional memory T cells following pathogenic infections in the absence of CD4(+) T cells. We show that following transplantation of allogeneic skin, in the absence of CD4(+) T cells, CD8(+) T cells become activated, proliferate, and expand exclusively in the draining lymph nodes and are able to infiltrate and reject skin allografts. CD44(+)CD8(+) T cells isolated 100 days after transplantation rapidly produce IFN-gamma following restimulation with alloantigen in vitro. In vivo CD44(+)CD8(+) T cells rejected donor-type skin allografts more rapidly than naive CD8(+) T cells demonstrating the ability of these putative memory T cells to mount an effective recall response in vivo. These data form the first direct demonstration that CD8(+) T cells are able to generate memory as well as effector cells in response to alloantigen during rejection in the complete absence of CD4(+) T cells. These data have important implications for the design of therapies to combat rejection and serve to reinforce the view that CD8(+) T cell responses to allografts require manipulation in addition to CD4(+) T cell responses to completely prevent the rejection of foreign organ transplants.

Allograft Rejection Mediated by Memory T Cells is Resistant to Regulation

Proceedings of the National Academy of Sciences of the United States of America. Dec, 2007  |  Pubmed ID: 18042727

Alloreactive memory T cells may be refractory to many of the tolerance-inducing strategies that are effective against naive T cells and thus present a significant barrier to long-term allograft survival. Because CD4(+)CD25(+) regulatory T cells (Tregs) are critical elements of many approaches to successful induction/maintenance of transplantation tolerance, we used MHC class I and II alloreactive TCR-transgenic models to explore the ability of antigen-specific Tregs to control antigen-specific memory T cell responses. Upon coadoptive transfer into RAG-1(-/-) mice, we found that Tregs effectively suppressed the ability of naive T cells to reject skin grafts, but neither antigen-unprimed nor antigen-primed Tregs suppressed rejection by memory T cells. Interestingly, different mechanisms appeared to be active in the ability of Tregs to control naive T cell-mediated graft rejection in the class II versus class I alloreactive models. In the former case, we observed decreased early expansion of effector cells in lymphoid tissue. In contrast, in the class I model, an effect of Tregs on early proliferation and expansion was not observed. However, at a late time point, significant differences in cell numbers were seen, suggesting effects on responding T cell survival. Overall, these data indicate that the relative resistance of both CD4(+) and CD8(+) alloreactive memory T cells to regulation may mediate resistance to tolerance induction seen in hosts with preexisting alloantigen-specific immunity and further indicate the multiplicity of mechanisms by which Tregs may control alloimmune responses in vivo.

Interleukin-23 and TH17 Cells in Transplantation Immunity: Does 23+17 Equal Rejection?

Transplantation. Nov, 2007  |  Pubmed ID: 17998858

Interleukin-23 (IL-23) and the recently discovered Th17 cells have been implicated in the pathogenesis of autoimmune diseases. This review will discuss current understanding of T-cell subsets in transplantation immunity and will explore the role of IL-23 and Th17 cells in allograft rejection, tolerance, and ischemia reperfusion injury.

Natural Killer T Cells: a Bridge to Tolerance or a Pathway to Rejection?

Transplantation. Sep, 2007  |  Pubmed ID: 17893598

Over the past 20 years, natural killer T (NKT) cells have been shown to play an important role in both innate and adaptive immune responses. In this review, the potential role of NKT cells in transplantation will be discussed, particularly their role in rejection and the induction of a state of tolerance.

Understanding FOXP3: Progress Towards Achieving Transplantation Tolerance

Transplantation. Aug, 2007  |  Pubmed ID: 17713426

Regulatory T cells (Treg) suppress immune responses, making them an exciting therapeutic target for achieving operational transplant tolerance. Recent observations have identified forkhead box P3 (FOXP3) as a master gene required for the development and function of Treg. Improving our understanding of FOXP3 may facilitate methods for identifying and generating Treg.

Transplantation Tolerance: Lessons from Experimental Rodent Models

Transplant International : Official Journal of the European Society for Organ Transplantation. Oct, 2007  |  Pubmed ID: 17711408

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models.

Dependency of the Trans Vivo Delayed Type Hypersensitivity Response on the Action of Regulatory T Cells: Implications for Monitoring Transplant Tolerance

Transplantation. Aug, 2007  |  Pubmed ID: 17700166

The trans vivo delayed-type hypersensitivity (DTH) assay has been used for monitoring the immune status of clinical transplant recipients. Here we tested the hypothesis that the assay can reveal control of allograft rejection by CD25CD4 regulatory T cells (Treg).

Interferon Gamma: Friend or Foe?

Transplantation. Jul, 2007  |  Pubmed ID: 17632413

Interferon gamma (IFN-gamma) can elicit an inflammatory TH1-driven immune response but has also been found to be necessary for long-term allograft survival induced by costimulation blockade. Recently, we have found that regulatory T cells rapidly and transiently produce IFN-gamma creating a microenvironment that can influence the function of antigen presenting cells (APCs), T-cell proliferation and activation as well as T-cell effector mechanisms, thereby controlling immune responses locally. Moreover, addition of IFN-gamma to cocultures of T cells and APCs can drive the generation of T cells with regulatory activity. Thus, the influence of IFN-gamma on the immune response to a transplant is likely to be context dependent.

Aircraft Accidents and Incidents Associated with Visual Effects from Bright Light Exposures During Low-light Flight Operations

Optometry (St. Louis, Mo.). Aug, 2007  |  Pubmed ID: 17662931

Preservation of optimal night vision is important for pilots operating aircraft in low-light conditions. This study investigates operational problems experienced by civilian airmen exposed to bright light sources while performing nighttime aviation activities.

Regulation of Transplant Arteriosclerosis by CD25+CD4+ T Cells Generated to Alloantigen in Vivo

Transplantation. Jun, 2007  |  Pubmed ID: 17565319

CD25+CD4+ regulatory T cells have been shown to suppress alloimmunity in various experimental settings. Here, we hypothesized that alloantigen-reactive regulatory T cells would reduce the severity of transplant arteriosclerosis.

Spleen Plays an Important Role in Maintaining Tolerance After Removal of the Vascularized Heart Graft

Transplantation. May, 2007  |  Pubmed ID: 17496540

This study addresses the question of the mechanism for maintaining tolerance to donor alloantigen in the absence of antigen and the role of secondary lymphoid tissues.

Embryonic Stem Cell Transplantation: Potential Applicability in Cell Replacement Therapy and Regenerative Medicine

Frontiers in Bioscience : a Journal and Virtual Library. May, 2007  |  Pubmed ID: 17485394

Embryonic stem cells are derived from the inner cell mass of the trophoblast, and have the ability to differentiate into all the tissues of the fetus. As such, their potential in cell replacement therapy and regenerative medicine has been widely acknowledged. Useful cell types such as neurons, cardiomyocytes, hepatocytes, pancreatic beta cells, and blood cells have all been successfully derived in the laboratory. Furthermore, embryonic stem cells may be utilized in novel immunomodulatory applications, such as hematopoietic chimerism strategies aimed at inducing tolerance to donor organ allografts. Unfortunately, progress in embryonic stem cell therapeutics continues to be hindered by haphazard differentiation and tumorigenesis; and the immune response to an embryonic stem cell-derived tissue graft is still an open question. This review summarizes the current state of embryonic stem cell research in regards to transplantation, highlighting the successes to date and the future obstacles yet to be overcome. Although embryonic stem cells are still far from their debut in the clinic, continued scientific advances engender optimism that they will eventually play an important role in cell replacement therapy and regenerative medicine.

Regulatory T Cells--a Journey from Rodents to the Clinic

Frontiers in Bioscience : a Journal and Virtual Library. May, 2007  |  Pubmed ID: 17485357

Over the past decade our understanding about a subset of T lymphocytes, now termed regulatory T cells (Tregs) and previously known as suppressor T cells, has increased immensely. Tregs can induce and maintain immune tolerance and have the capacity to facilitate antigen-specific long-term graft survival successfully in animals receiving allogeneic organ transplants. The development of approaches to generate alloantigen reactive Tregs would provide an exciting and effective adjunct or alternative therapy to the life-long program of immunosuppression currently necessary to prevent graft rejection in the clinical setting. This review will focus on how rodent experimental models have helped us to figure out how Tregs could be induced in humans and harnessed to enable long-term transplant acceptance.

Functional Dichotomy of NK Cells in Organ Transplantation

Expert Review of Clinical Immunology. May, 2007  |  Pubmed ID: 20477669

Evaluation of: Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J. Exp. Med. 203, 1851-1858 (2006). Natural killer (NK) cells have the potential to display different functional activities after transplantation. The traditional view is that NK cells have the capacity to contribute to rejection by facilitating the activation/differentiation of leukocytes that destroy the graft. By contrast, in the article under review, a novel role for NK cells was identified in the setting of costimulation blockade where alloreactive NK cells of recipient origin were found to have the capacity to kill donor-derived antigen-presenting cells, thereby reducing T-cell priming and promoting long-term skin graft acceptance.

Clinical, Immunological, and Pathological Aspects of Operational Tolerance After Pediatric Living-donor Liver Transplantation

Transplant Immunology. Feb, 2007  |  Pubmed ID: 17306739

In the setting of our pediatric living-donor liver transplantation (LDLT), 87 patients (15.0% of all the patients: significantly higher proportion, compared with those of other transplant centers) achieved complete withdrawal of immunosuppression, which is referred to as "operational tolerance". Immunosuppressants were completely discontinued for 54 patients as scheduled, and for 33 because of EBV infection or other complications. Immunological analyses of the peripheral blood derived from operationally tolerant patients demonstrated that non-deletional tolerance takes place in which potentially reactive T cells to donor-antigens remain physically in the immune repertoire, but specifically suppressed by certain mechanisms. Not only CD4(+)CD25(high+) T cells were increased in the proportion in the tolerant patients' peripheral lymphocytes and suppressed MLR specifically to the donor antigen, but also FOXP3 expressing cells were present within the tolerant liver. Thus, among several mechanisms accounting for non-deletional tolerance, Tregs are likely to involve at least in part in our tolerant patients. Vdelta1gammadeltaT cells, a subset of gammadeltaT cells, which otherwise reside mainly in the intestine, emerge into the peripheral blood during successful pregnancy but not abortive pregnancy. Since Vdelta1gammadeltaT cells produce massive IL-10, it is proposed that Vdelta1gammadeltaT cells induce fetomaternal tolerance by promoting Th2 immune deviation. Consistent with pregnancy, IL-10 producing Vdelta1gammadeltaT cells emerge into the blood of our tolerant patients. This may reflect a common feature between fetomaternal tolerance and transplant tolerance. We began protocol biopsy in post-LDLT patients who exhibit normal liver function from January 2003. Operationally tolerant patients, albeit showing normal liver function, exhibited decrease in size and increase in number of the bile duct and the fibrosis to a greater extent, compared with patients on maintenance immunosuppression. This warrants serial protocol biopsy before and after complete cessation of immunosuppression even in the presence of normal liver function.

Introduction of the President of The Transplantation Society, Nicholas Tilney

Transplantation. Dec, 2008  |  Pubmed ID: 19104395

Neutralizing Interleukin-4 Prevents Transplant Arteriosclerosis Mediated by Indirect Pathway T Cells Under CD40-CD154 Costimulation Blockade

Transplantation. Dec, 2008  |  Pubmed ID: 19077898

Blockade of the CD40-CD154 costimulatory pathway can prolong allograft survival, but does not prevent the development of transplant arteriosclerosis in several models. In this study, we investigated the mechanisms of CD40-CD154-independent transplant arteriosclerosis in major histocompatibility complex (MHC)-class I-mismatched aortic allografts.

Exogenous IFN-gamma Ex Vivo Shapes the Alloreactive T-cell Repertoire by Inhibition of Th17 Responses and Generation of Functional Foxp3+ Regulatory T Cells

European Journal of Immunology. Sep, 2008  |  Pubmed ID: 18792404

Interferon (IFN)-gamma was originally characterized as a pro-inflammatory cytokine with T helper type 1-inducing activity, but subsequent work has demonstrated that mice deficient in IFN-gamma or IFN-gamma receptor show exacerbated inflammatory responses and accelerated allograft rejection, suggesting that IFN-gamma also has important immunoregulatory functions. Here, we demonstrate that ex vivo IFN-gamma conditioning of CD4 T cells driven by allogeneic immature dendritic cells (DC) results in the emergence of a Foxp3(+) regulatory T-cell (Treg)- dominant population that can prevent allograft rejection. The development of this population involves conversion of non-Treg precursors, preferential induction of activation-induced cell death within the non-Treg population and suppression of Th2 and Th17 responses. The suppressive activity of IFN-gamma is dependent on the transcription factor signal transducer and activator of transcription 1 and is mediated by induced nitric oxide. These data indicate not only how IFN-gamma could be used to shape beneficial immune responses ex vivo for possible cell therapy but also provide some mechanistic insights that may be relevant to exacerbated inflammatory responses noted in several autoimmune and transplant models with IFN-gamma deficiency.

Increased Transplant Arteriosclerosis in the Absence of CCR7 is Associated with Reduced Expression of Foxp3

Transplantation. Aug, 2008  |  Pubmed ID: 18724230

The chemokine receptor CCR7 plays a pivotal role in the homing of naïve T cells and regulatory T cells to secondary lymphoid organs and the migration of dendritic cells into afferent lymphatic vessels. Antigen presentation, T cell recruitment, and expansion of regulatory cells are crucial events in establishing and controlling chronic allograft dysfunction. In this study, we report an important role for chemokine receptor CCR7 in the development of transplant arteriosclerosis.

Interferon-gamma Conditioning Ex Vivo Generates CD25+CD62L+Foxp3+ Regulatory T Cells That Prevent Allograft Rejection: Potential Avenues for Cellular Therapy

Transplantation. Aug, 2008  |  Pubmed ID: 18724229

Regulatory T cells (Treg) play important roles in preventing autoimmunity, graft-versus host disease and transplant rejection. In rodent transplant models, tolerance induction strategies can induce graft protective CD25CD4 Treg in vivo but therapeutic exploitation of active regulation will more likely depend on protocols that allow generation or selection of regulatory cells ex vivo for use as a cellular therapy. We have used adoptive transfer skin and islet allograft models to identify, develop and evaluate ex vivo protocols that generate donor-reactive, adaptive Treg.

Laser Exposure Incidents: Pilot Ocular Health and Aviation Safety Issues

Optometry (St. Louis, Mo.). Sep, 2008  |  Pubmed ID: 18722964

A database of aviation reports involving laser illumination of flight crewmembers has been established and maintained at the Civil Aerospace Medical Institute. A review of recent laser illumination reports was initiated to investigate the significance of these events.

Regulatory T Cells: Hypes and Limitations

Current Opinion in Organ Transplantation. Aug, 2008  |  Pubmed ID: 18685326

In recent years there has been increased interest in understanding the physiology and function of regulatory T cells. In this review we focus on the characterization of regulatory T-cell subsets and their potential therapeutic use in organ transplantation.

Embryonic Stem Cells and Their Differentiated Derivatives Have a Fragile Immune Privilege but Still Represent Novel Targets of Immune Attack

Stem Cells (Dayton, Ohio). Aug, 2008  |  Pubmed ID: 18535153

Embryonic stem cells (ESCs) offer an attractive potential in cell replacement therapy and regenerative medicine because of their inherent plasticity and ability to self-renew. However, the immunological response against transplanted ESC-derived allografts requires further evaluation. In this study, we showed that ESCs expressing the major histocompatibility complex class I molecule H2K(b) escape immune recognition by H2K(b)-reactive CD8(+) T cells, irrespective of H2K(b) expression levels. In the face of more robust immunological challenge, however, evidence of ESC allograft rejection becomes apparent. We further assessed the adaptive immune response against terminally differentiated insulin-producing tissue derived from an ESC source to examine the potential future applicability of this tissue as a beta-cell replacement therapy for type 1 diabetes mellitus. The functional ESC-derived insulin-producing tissue was infiltrated by alloreactive T cells and rejected in immunocompetent hosts. Hence, although ESCs and their terminally differentiated derivatives may possess a fragile immune privilege, they still represent novel targets of attack by elements of the immune system and are rejected. These findings provide insight into the mechanisms of adaptive immunity toward ESCs and their derivatives. Disclosure of potential conflicts of interest is found at the end of this article.

Exhaustive Differentiation of Alloreactive CD8+ T Cells: Critical for Determination of Graft Acceptance or Rejection

Transplantation. May, 2008  |  Pubmed ID: 18475193

The precise role that CD8+ T cells play in the rejection and acceptance of different types of allograft is unclear and has been shown to vary between donor-recipient combinations.

Anti-CD4-mediated Selection of Treg in Vitro - in Vitro Suppression Does Not Predict in Vivo Capacity to Prevent Graft Rejection

European Journal of Immunology. Jun, 2008  |  Pubmed ID: 18465768

Regulatory T cells (Treg) have been shown to play a role in the prevention of autoimmune diseases and transplant rejection. Based on an established protocol known to generate alloantigen reactive Treg in vivo, we have developed a strategy for the in vitro selection of Treg. Stimulation of unfractionated CD4(+) T cells from naive CBA.Ca (H2(k)) mice with C57BL/10 (H2(b)) splenocytes in the presence of an anti-CD4 antibody, YTS 177, resulted in the selection of Treg able to inhibit proliferation of naive T cells. In vivo, the cells were able to prevent rejection of 80% C57BL/10 skin grafts when co-transferred to CBA.Rag(-/-) mice together with naive CD45RB(high)CD4(+) cells. Purification of CD62L(+)CD25(+)CD4(+) cells from the cultures enriched for cells with regulatory activity; as now 100% survival of C57BL/10 skin grafts was achieved. Furthermore, differentiation of Treg could be also achieved when using purified CD25(-)CD4(+) naive T cells as a starting population. Interestingly, further in vitro expansion resulted in a partial loss of CD4(+) cells expressing both CD62L and CD25 and abrogation of their regulatory activity in vivo. This study shows that alloantigen stimulation in the presence of anti-CD4 in vitro provides a simple and effective strategy to generate alloreactive Treg.

Location and Time-dependent Control of Rejection by Regulatory T Cells Culminates in a Failure to Generate Memory T Cells

Journal of Immunology (Baltimore, Md. : 1950). May, 2008  |  Pubmed ID: 18453583

Adaptive CD25(+)CD4(+) regulatory T cells (Treg) can be induced following exposure to alloantigen and may function alongside naturally occurring Treg to suppress allograft rejection when present in sufficient numbers. However, the location of the Treg as they function in vivo and the mechanisms used to control donor-reactive T cells remains ill-defined. In this study, we used a CD8(+) TCR transgenic model of skin allograft rejection to characterize in vivo activity of donor-reactive Treg cells during induction of transplantation tolerance. We demonstrate that, initially after skin transplantation, Treg attenuate the priming of donor-reactive naive CD8(+) T cells in the lymphoid tissue draining the graft site. However, with time, peripheral suppression is overcome despite the continued presence of Treg, resulting in the priming of donor-reactive CD8(+) T cells and graft infiltration by the resultant effector T cells and induction of a "Tc1-like" intragraft gene expression profile. These intragraft effector CD8(+) T cells are then prevented from eliciting rejection by Treg that simultaneously infiltrate the skin allografts, resulting in a failure to generate donor-reactive memory CD8(+) T cells. Overall, these data demonstrate for the first time that donor-reactive Treg can suppress allograft rejection using distinct mechanisms at different sites in vivo with the overall outcome of preventing the generation of donor-reactive memory T cells.

A Comparison of Protocols Used to Generate Insulin-producing Cell Clusters from Mouse Embryonic Stem Cells

Stem Cells (Dayton, Ohio). May, 2008  |  Pubmed ID: 18323410

Embryonic stem cells (ESCs) have the capacity to generate a panoply of tissue types and may therefore provide an alternative source of tissue in regenerative medicine to treat potentially debilitating conditions like Type 1 diabetes mellitus. However, the ability of mouse ESCs to generate insulin-producing cell clusters (IPCCs) remains highly contentious. In an attempt to clarify this issue, three protocols for the ESC-based generation of IPCCs (referred to as Blyszczuk, Hori, and Lumelsky protocols) were modified and evaluated for their ability to express pancreatic islet genes and proteins and their capacity to function. Herein, we show that the Blyszczuk protocol reproducibly generated IPCCs with gene-expression characteristics that were qualitatively and quantitatively most reminiscent of those found in pancreatic islets. Furthermore, compared to the Hori and Lumelsky protocols, Blyszczuk-derived IPCCs exhibited superior expression of c-peptide, a by-product of de novo insulin synthesis. Functionally, Blyszczuk IPCCs, in contrast to Hori and Lumelsky IPCCs, were able to transiently restore normal blood glucose levels in diabetic mice (<1 week). Longer normoglycemic rescue (>2 weeks) was also achieved in a third of diabetic recipients receiving Blyszczuk IPCCs. Yet Blyszczuk IPCCs were less able to rescue experimental diabetes than isolated syngeneic pancreatic islet tissue. Therefore, depending on the mode of differentiation, ESCs can be driven to generate de novo IPCCs that possess limited functionality. Further modifications to differentiation protocols will be essential to improve the generation of functional IPCCs from mouse ESCs.

Investigation into the Onset and Progression of Transplant Arteriosclerosis in a Mice Aortic Retransplantation Model

Microsurgery. 2008  |  Pubmed ID: 18253942

Long-term function of vascularized human organ grafts is often limited by transplant arteriosclerosis and can lead to graft failure. Here, we have analyzed the impact of an initial rejection episode on the later development of transplant arteriosclerosis. Following transplantation of allogeneic abdominal aortic segments in mice, aortic grafts were retransplanted into either immunodeficient or syngeneic recipients. Retransplantation of grafts from immunocompetent into immunodeficient mice as early as 2 days after the primary transplant resulted in intimal proliferation and obstruction of the graft lumen 30 days after the primary transplant. In contrast, retransplantation of the grafts into donor syngeneic B10 recipients within 7 days did not result in the development of transplant arteriosclerosis. These data suggest that the adaptive immune system can induce intimal proliferation by an initial lethal hit that is sustained by the innate response. However our data demonstrate that development of chronic rejection can be inhibited, in this case by retransplantation into a syngeneic host.

An Investigation to Assess the Potential of CD25highCD4+ T Cells to Regulate Responses to Donor Alloantigens in Clinically Stable Renal Transplant Recipients

Transplant International : Official Journal of the European Society for Organ Transplantation. Jan, 2008  |  Pubmed ID: 17887959

Regulatory T cells are enriched within CD25(high)CD4(+) leukocytes, however their role in renal transplant recipients with stable function vs. recipients with biopsy-proven chronic allograft dysfunction remains unclear. We therefore studied the number, phenotype, and function of CD25(high)CD4(+) cells in the peripheral blood of 30 renal transplant recipients of living-related grafts, comprising 15 rejection-free recipients with stable graft function (Group A) and 15 with biopsy-proven chronic graft dysfunction (Group B). A higher absolute number of CD25(high)CD4(+) cells were present in the peripheral blood of rejection-free recipients (Group A) vs. those recipients with chronic graft dysfunction (Group B) (P = 0.019); but there was no significant difference with healthy volunteers (P = 0.084). In carboxyfluorescein diacetate succinimidyl ester-mixed leukocyte culture assays, depletion of CD25(high)CD4(+) revealed active regulation in 11 (74%) of 15 rejection-free recipient samples (Group A) in response to donor- but not third party-leukocytes, whereas no regulatory activity was observed in any samples from recipients with chronic graft dysfunction (Group B). In conclusion, these data provide evidence for the presence of an increased number of CD25(high)CD4(+) T cells with donor-specific regulatory activity in the peripheral blood of renal transplant recipients with stable graft function compared with recipients with chronic graft dysfunction.

Regulatory T Cells in Transplantation: Transferring Mouse Studies to the Clinic

Transplantation. Nov, 2009  |  Pubmed ID: 19898199

Switching the balance from rejection of major histocompatibility-mismatched grafts toward long-term tolerance of donor grafts, with the need for minimal immunosuppressive drugs, is a major transplantation goal. Regulatory T cells (Treg) can induce and maintain antigen-specific immune tolerance and facilitate allogeneic graft survival successfully in animals. This review will focus on the valuable insights experimental mouse models have given us into the effects of currently used immunosuppressive reagents on Treg, the Treg transcription factor forkhead box P3, and strategies to expand or induce alloantigen-reactive Treg in vivo and in vitro. These have facilitated the translation of strategies for promoting transplantation tolerance towards a new clinical era.

Mesenchymal Stem Cells Prevent the Rejection of Fully Allogenic Islet Grafts by the Immunosuppressive Activity of Matrix Metalloproteinase-2 and -9

Diabetes. Aug, 2009  |  Pubmed ID: 19509016

Mesenchymal stem cells (MSCs) are known to be capable of suppressing immune responses, but the molecular mechanisms involved and the therapeutic potential of MSCs remain to be clarified.

Donor Reactive Regulatory T Cells

Current Opinion in Organ Transplantation. Aug, 2009  |  Pubmed ID: 19448539

Donor reactive regulatory T cells (Treg) play an important role in tolerance induction and maintenance in experimental transplant models. In this review we focus on the formation of the donor reactive Treg pool and explore the potential of these cells for therapeutic application in clinical transplantation.

Variation in MHC Expression Between Undifferentiated Mouse ES Cells and ES Cell-derived Insulin-producing Cell Clusters

Transplantation. May, 2009  |  Pubmed ID: 19424028

The progeny of embryonic stem (ES) cells may eventually be used to replace damaged tissues in transplantation, yet their immunogenicity remains ill-defined. The major histocompatibility complex (MHC) is a determinant of immunogenicity in transplantation.

Analysis of the Peripheral T-cell Repertoire in Kidney Transplant Patients

European Journal of Immunology. Nov, 2010  |  Pubmed ID: 21061447

The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8(+) /CD4(+) T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the "suspicious" form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation.

Anti-OX40 Prevents Effector T-cell Accumulation and CD8+ T-cell Mediated Skin Allograft Rejection

Transplantation. Dec, 2010  |  Pubmed ID: 21037534

OX40 is a member of the tumor necrosis factor receptor superfamily and is a potent T-cell costimulatory molecule. Although the impact of blockade of the OX40-OX40L pathway has been documented in models of autoimmune disease, the effect on allograft rejection is less well defined.

Mesenchymal Stromal Cells: Facilitators of Successful Transplantation?

Cell Stem Cell. Oct, 2010  |  Pubmed ID: 20887949

Mesenchymal stromal/stem cells (MSCs) possess immunomodulatory and reparative properties. Through specific interactions with immune cells that participate in both innate and adaptive responses, MSCs exposed to an inflammatory microenvironment can downregulate many immune effector functions. Clinical trials focusing on MSCs to treat graft-versus-host disease (GvHD) and autoimmune diseases are underway. Current analyses suggest that MSCs will improve cell and solid organ transplantation by ameliorating rejection and possibly eliminating the requirement for prolonged regimens of conventional immunosuppressive drugs. This review examines the in vitro and in vivo evidence for the clinical use of bone marrow derived MSCs.

CD4+ Regulatory T Cells in Solid Organ Transplantation

Current Opinion in Organ Transplantation. Dec, 2010  |  Pubmed ID: 20881492

Solid organ transplantation is the most effective treatment for end-stage organ failure, but the long-term outcomes remain suboptimal. CD4 regulatory T cells (Tregs) are emerging as a potential therapy to facilitate long-term allograft survival. This review provides a general overview of the biology of CD4 Tregs and then goes on to discuss the most relevant and recent experimental and clinical evidence for their therapeutic use in solid organ transplantation.

In Vivo Quantification of VCAM-1 Expression in Renal Ischemia Reperfusion Injury Using Non-invasive Magnetic Resonance Molecular Imaging

PloS One. Sep, 2010  |  Pubmed ID: 20877722

Vascular cell adhesion molecule-1 (VCAM-1) is upregulated in ischemia reperfusion injury (IRI), persisting after restoration of blood flow. We hypothesized that microparticles of iron oxide targeting VCAM-1 (VCAM-MPIO) would depict "ischemic memory" and enable in vivo assessment of VCAM-1 expression.

T Regulatory Cells and the Control of Alloimmunity: from Characterisation to Clinical Application

Current Opinion in Immunology. Oct, 2010  |  Pubmed ID: 20869224

T regulatory cells (Treg) play an important role in the induction and maintenance of immunological tolerance. Recent findings in experimental transplant models combined with the development of functional reporter mice have opened new avenues to study Treg biology and their therapeutic potential. In particular, recent advances in understanding Treg function and lineage stability revealed unexpected plasticity of this lineage. Nevertheless, pre-clinical and pilot clinical trials using Treg cells as cellular therapies have been initiated suggesting the safety and feasibility of such treatment.

Regulatory T Cells Can Prevent Memory CD8+ T-cell-mediated Rejection Following Polymorphonuclear Cell Depletion

European Journal of Immunology. Nov, 2010  |  Pubmed ID: 20865790

Accumulating evidence suggests that alloreactive memory T cells (Tm) may form a barrier to tolerance induction in large animals and humans due in part to a resistance to suppression by Treg. However, why Tm are resistant to regulation and how the Tm response to an allograft differs from that of naïve T cells, which are amenable to suppression by Treg, remains unknown. Here, we show that accelerated graft rejection mediated by CD8(+) Tm was due to the enhanced recruitment of PMN to allografts in a mouse skin allograft model. Importantly, depletion of PMN slowed the kinetics of (but did not prevent) rejection mediated by Tm and created a window of opportunity that allowed subsequent suppression of rejection by Treg. Taken together, we conclude that CD8(+) Tm are not intrinsically resistant to suppression by Treg but may rapidly inflict substantial graft damage before the establishment of regulatory mechanisms. These data suggest that if Tm responses can be attenuated transiently following transplantation, Treg may be able to maintain tolerance through the suppression of both memory and naïve alloreactive T-cell responses in the long term.

The Impact of Th17 Cells on Transplant Rejection and the Induction of Tolerance

Current Opinion in Organ Transplantation. Aug, 2010  |  Pubmed ID: 20616728

This review aims to provide an overview of the latest evidence for the involvement of Th17 cells in the rejection of solid organ allografts. It will also consider the implications of the relationship between the differentiation pathways of Th17 and regulatory T cells (Tregs), as well as their plasticity in the context of transplantation tolerance.

Characteristics of the Early Immune Response Following Transplantation of Mouse ES Cell Derived Insulin-producing Cell Clusters

PloS One. Jun, 2010  |  Pubmed ID: 20532031

The fully differentiated progeny of ES cells (ESC) may eventually be used for cell replacement therapy (CRT). However, elements of the innate immune system may contribute to damage or destruction of these tissues when transplanted.

Development of a Cross-platform Biomarker Signature to Detect Renal Transplant Tolerance in Humans

The Journal of Clinical Investigation. Jun, 2010  |  Pubmed ID: 20501943

Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.

In Vivo Prevention of Transplant Arteriosclerosis by Ex Vivo-expanded Human Regulatory T Cells

Nature Medicine. Jul, 2010  |  Pubmed ID: 20473306

Transplant arteriosclerosis is the hallmark of chronic allograft dysfunction (CAD) affecting transplanted organs in the long term. These fibroproliferative lesions lead to neointimal thickening of arteries in all transplanted allografts. Luminal narrowing then leads to graft ischemia and organ demise. To date, there are no known tolerance induction strategies that prevent transplant arteriosclerosis. Therefore, we designed this study to test the hypothesis that human regulatory T cells (T(reg) cells) expanded ex vivo can prevent transplant arteriosclerosis. Here we show the comparative capacity of T(reg) cells, sorted via two separate strategies, to prevent transplant arteriosclerosis in a clinically relevant chimeric humanized mouse system. We found that the in vivo development of transplant arteriosclerosis in human arteries was prevented by treatment of ex vivo-expanded human T(reg) cells. Additionally, we show that T(reg) cells sorted on the basis of low expression of CD127 provide a more potent therapy to conventional T(reg) cells. Our results demonstrate that human T(reg) cells can inhibit transplant arteriosclerosis by impairing effector function and graft infiltration. We anticipate our findings to serve as a foundation for the clinical development of therapeutics targeting transplant arteriosclerosis in both allograft transplantation and other immune-mediated causes of vasculopathy.

CD4+ Regulatory T Cells Generated in Vitro with IFN-{gamma} and Allogeneic APC Inhibit Transplant Arteriosclerosis

The American Journal of Pathology. Jul, 2010  |  Pubmed ID: 20472892

We have developed a method to generate alloreactive regulatory T cells in vitro in the presence of interferon (IFN)-gamma and donor antigen presenting cells (APCs). We hypothesized that these IFN-gamma-conditioned T cells (Tcon) would reduce transplantation-associated arteriosclerosis. Tcon were generated from mouse (CBA.Ca, H-2(k)) CD4(+) T cells cultured in the presence of IFN-gamma for 14 days. These cultures were pulsed with bone marrow-derived B6 (H-2(b)) APC. 1 x 10(5) CD25(-)CD4(+) effector T cells from naive H-2(k) mice were then cotransferred with 4 x 10(5) Tcon into CBA-rag(-/-) mice. One day later, these mice received a fully allogenic B6 CD31(-/-) abdominal aorta transplant. Transfer of CD25(-)CD4(+) effectors resulted in 29.7 +/- 14.5% luminal occlusion of allogeneic aortic grafts after 30 days. Cotransfer of Tcon reduced this occlusion to 11.7 +/- 13.1%; P < 0.05. In addition, the CD31(-) donor endothelium was fully repopulated by CD31(+) recipient endothelial cells in the absence of Tcon, but not in the presence of Tcon. In some experiments, we cotransplanted B6 skin with aortic grafts to ensure enhanced reactivation of the regulatory cells, which led to an additional reduction in vasculopathy (1.9 +/- 3.0% luminal occlusion). In the presence of Tcon, CD4(+) T cell infiltration into grafts was markedly reduced by a regulatory mechanism that included reduced priming and proliferation of CD25(-)CD4(+) effectors. These data illustrate the potential of ex vivo generated regulatory T cells for the inhibition of transplant-associated vasculopathy.

Intravenous Immunoglobulins Promote Skin Allograft Acceptance by Triggering Functional Activation of CD4+Foxp3+ T Cells

Transplantation. Jun, 2010  |  Pubmed ID: 20463648

Intravenous immunoglobulins (IVIg) therapy is effective as a treatment for T-cell-mediated immune diseases, but whether and how IVIg suppress allogeneic T-cell responses is largely unknown.

Role of T Cells in Graft Rejection and Transplantation Tolerance

Expert Review of Clinical Immunology. Jan, 2010  |  Pubmed ID: 20383898

Transplantation is the most effective treatment for end-stage organ failure, but organ survival is limited by immune rejection and the side effects of immunosuppressive regimens. T cells are central to the process of transplant rejection through allorecognition of foreign antigens leading to their activation, and the orchestration of an effector response that results in organ damage. Long-term transplant acceptance in the absence of immunosuppressive therapy remains the ultimate goal in the field of transplantation and many studies are exploring potential therapies. One promising cellular therapy is the use of regulatory T cells to induce a state of donor-specific tolerance to the transplant. This article first discusses the role of T cells in transplant rejection, with a focus on the mechanisms of allorecognition and the alloresponse. This is followed by a detailed review of the current progress in the field of regulatory T-cell therapy in transplantation and the translation of this therapy to the clinical setting.

Mesenchymal Stem-cell Immunosuppressive Capabilities: Therapeutic Implications in Islet Transplantation

Transplantation. Feb, 2010  |  Pubmed ID: 20145515

Mesenchymal stem cells (MSCs) are known to be capable of suppressing immune responses and offer therapeutic potential for achieving transplantation tolerance. This review will discuss the impacts of MSCs on transplant immunity and focus on the potential role of MSCs in protecting islet grafts from both rejection and autoimmune attack.

Alpha-1,2-mannosidase and Hence N-glycosylation Are Required for Regulatory T Cell Migration and Allograft Tolerance in Mice

PloS One. Jan, 2010  |  Pubmed ID: 20126660

Specific immunological unresponsiveness to alloantigens can be induced in vivo by treating mice with a donor alloantigen in combination with a non-depleting anti-CD4 antibody. This tolerance induction protocol enriches for alloantigen reactive regulatory T cells (Treg). We previously demonstrated that alpha-1,2-mannosidase, an enzyme involved in the synthesis and processing of N-linked glycoproteins, is highly expressed in tolerant mice, in both graft infiltrating leukocytes and peripheral blood lymphocytes.

Immune Phenotype Predicts Risk for Posttransplantation Squamous Cell Carcinoma

Journal of the American Society of Nephrology : JASN. Apr, 2010  |  Pubmed ID: 20110382

Cutaneous squamous cell cancer (SCC) affects up to 30% of kidney transplant recipients (KTRs) within 10 years of transplantation. There are no reliable clinical tests that predict those who will develop multiple skin cancers. High numbers of regulatory T cells associate with poor prognosis for patients with cancer in the general population, suggesting their potential as a predictive marker of cutaneous SCC in KTRs. We matched KTRs with (n = 65) and without (n = 51) cutaneous SCC for gender, age, and duration of immunosuppression and assessed several risk factors for incident SCC during a median follow-up of 340 days. Greater than 35 peripheral FOXP3(+)CD4(+)CD127(low) regulatory T cells/microl, <100 natural killer cells/microl, and previous SCC each significantly associated with increased risk for new cutaneous SCC development (hazard ratio [HR] 2.48 [95% confidence interval (CI) 1.04 to 5.98], HR 5.6 [95% CI 1.31 to 24], and HR 1.33 [95% CI 1.15 to 1.53], respectively). In addition, the ratio of CD8/FOXP3 expression was significantly lower in cutaneous SCC excised from KTRs (n = 25) compared with matched SCC from non-KTRs (n = 25) and associated with development of new cutaneous SCCs. In summary, monitoring components of the immune system can predict development of cutaneous SCC among KTRs.

Immunosenescence Increases the Rate of Acceptance of Kidney Allotransplants in Elderly Recipients Through Exhaustion of CD4+ T-cells

Mechanisms of Ageing and Development. Feb, 2010  |  Pubmed ID: 20060852

Compromised immunity is the hallmark of ageing. Paradoxically, it may be "an ally" in facilitating acceptance of allogeneic grafts in the elderly. In this retrospective study we looked for biomarkers of immunosenescence that distinguish elderly recipients less prone to reject kidney allografts. Recruited kidney recipients aged > or = 60 or < 60 were designated 'elderly' and 'young', respectively. Both age-groups were divided according to the history of acute rejection. The phenotype, length of telomeres, expression of FoxP3 and proliferative responses were assessed in CD4(+) and CD8(+) T-cell subsets. In addition, IL6, IL10 and TGFbeta were measured on the level of mRNA and serum protein. Acute-rejection-free history in elderly transplant recipients was associated with short telomeres, a decreased proportion of CD28(+) T-cells associated with CMV-seropositivity and low proliferation of CD4(+) T-cells. In contrast, elderly recipients who experienced acute rejection kept preserved telomere length, had a higher number of functional CD4(+)CD28(+) cells and exhibited vigorous proliferation in vitro. These differences were not found in the young group. The major conclusion of this study is that the impaired condition of CD4(+) T-cells, so-called immunosenescence, renders transplant recipients less responsive to an allogeneic kidney graft, an effect that was limited to transplant recipients of > 60 years of age.

The Discovery of Immunological Tolerance: Now More Than Just a Laboratory Solution

Journal of Immunology (Baltimore, Md. : 1950). Jan, 2010  |  Pubmed ID: 20028657

Laser Illumination of Flight Crewmembers by Altitude and Chronology of Occurrence

Aviation, Space, and Environmental Medicine. Nov, 2011  |  Pubmed ID: 22097641

The illumination of flight crew personnel by lasers while they perform landing and departure maneuvers has concerned the aviation community for the past two decades. This study examines the frequency of illumination events in the United States by altitude and chronology of occurrence to determine where and when aviators and the flying public may be at greatest risk.

How Regenerative Medicine May Contribute to the Achievement of an Immunosuppression-free State

Transplantation. Oct, 2011  |  Pubmed ID: 21989270

IL-33 Expands Suppressive CD11b+ Gr-1(int) and Regulatory T Cells, Including ST2L+ Foxp3+ Cells, and Mediates Regulatory T Cell-dependent Promotion of Cardiac Allograft Survival

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2011  |  Pubmed ID: 21949025

IL-33 administration is associated with facilitation of Th2 responses and cardioprotective properties in rodent models. However, in heart transplantation, the mechanism by which IL-33, signaling through ST2L (the membrane-bound form of ST2), promotes transplant survival is unclear. We report that IL-33 administration, while facilitating Th2 responses, also increases immunoregulatory myeloid cells and CD4(+) Foxp3(+) regulatory T cells (Tregs) in mice. IL-33 expands functional myeloid-derived suppressor cells, CD11b(+) cells that exhibit intermediate (int) levels of Gr-1 and potent T cell suppressive function. Furthermore, IL-33 administration causes an St2-dependent expansion of suppressive CD4(+) Foxp3(+) Tregs, including an ST2L(+) population. IL-33 monotherapy after fully allogeneic mouse heart transplantation resulted in significant graft prolongation associated with increased Th2-type responses and decreased systemic CD8(+) IFN-γ(+) cells. Also, despite reducing overall CD3(+) cell infiltration of the graft, IL-33 administration markedly increased intragraft Foxp3(+) cells. Whereas control graft recipients displayed increases in systemic CD11b(+) Gr-1(hi) cells, IL-33-treated recipients exhibited increased CD11b(+) Gr-1(int) cells. Enhanced ST2 expression was observed in the myocardium and endothelium of rejecting allografts, however the therapeutic effect of IL-33 required recipient St2 expression and was dependent on Tregs. These findings reveal a new immunoregulatory property of IL-33. Specifically, in addition to supporting Th2 responses, IL-33 facilitates regulatory cells, particularly functional CD4(+) Foxp3(+) Tregs that underlie IL-33-mediated cardiac allograft survival.

Cutting Edge: Immunological Consequences and Trafficking of Human Regulatory Macrophages Administered to Renal Transplant Recipients

Journal of Immunology (Baltimore, Md. : 1950). Sep, 2011  |  Pubmed ID: 21804023

Regulatory macrophages (M regs) were administered to two living-donor renal transplant recipients. Both patients were minimized to low-dose tacrolimus monotherapy within 24 wk of transplantation and subsequently maintained excellent graft function. After central venous administration, most M regs remained viable and were seen to traffic from the pulmonary vasculature via the blood to liver, spleen, and bone marrow. By 1 y posttransplantation, both patients displayed patterns of peripheral blood gene expression converging upon the IOT-RISET signature. Furthermore, both patients maintained levels of peripheral blood FOXP3 and TOAG-1 mRNA expression within the range consistent with nonrejection. It is concluded that M regs warrant further study as a potential immune-conditioning therapy for use in solid-organ transplantation. The results of this work are being used to inform the design of The ONE Study, a multinational clinical trial of immunomodulatory cell therapy in renal transplantation.

Regulatory T Cells As Modulators of Chronic Allograft Dysfunction

Current Opinion in Immunology. Oct, 2011  |  Pubmed ID: 21752619

Chronic allograft dysfunction (CAD) in solid organ transplantation is a principal cause of patient morbidity and late allograft loss. The pathogenesis of CAD is largely secondary to chronic damage by the adaptive immune system and long-term immunosuppression. Manipulating these factors may be possible with the use of regulatory T cells (Treg), which have the ability to suppress specific immune responses and therefore potentially remove the need for immunosuppressive drugs. Studies of CAD in experimental models have demonstrated the capacity for both mouse and human Treg cellular therapy to prevent the development of some manifestations of CAD. Furthermore, a role for Treg has been demonstrated in clinically tolerant transplant patients. Certain immunosuppressive therapies are also proving to be 'Treg friendly' and may be helpful in promoting Treg while maintaining other immunosuppressive activity. With this in mind, monitoring for biomarkers of operational tolerance with tailored immunosuppressive therapy or controlled weaning in conjunction with Treg cellular therapy may be a useful strategy to pursue.

Moving to Tolerance: Clinical Application of T Regulatory Cells

Seminars in Immunology. Aug, 2011  |  Pubmed ID: 21620722

Decreasing the incidence of chronic rejection and reducing the need for life-long immunosuppression remain important goals in clinical transplantation. In this article, we will review how regulatory T cells (Treg) came to be recognized as an attractive way to prevent or treat allograft rejection, the ways in which Treg can be manipulated or expanded in vivo, and the potential of in vitro expanded/generated Treg for cellular therapy. We will describe the first regulatory T cell therapies that have been or are in the process of being conducted in the clinic as well as the safety concerns of such therapies and how outcomes may be measured.

Functional Regulatory T Cells Produced by Inhibiting Cyclic Nucleotide Phosphodiesterase Type 3 Prevent Allograft Rejection

Science Translational Medicine. May, 2011  |  Pubmed ID: 21593400

Regulatory T cells (T(regs)) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring T(regs), an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen-presenting cells (APCs) under conditions that lead to the generation or expansion of donor-reactive, adaptive T(regs). Here we demonstrate that stimulation of mouse CD4(+) T cells by immature allogeneic dendritic cells combined with pharmacological inhibition of phosphodiesterase 3 (PDE) resulted in a functional enrichment of Foxp3(+) T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4(+) effectors or donor-reactive CD8(+) T cell receptor transgenic T cells and inhibited both effector cell proliferation and T cell priming for interferon-γ production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3(+) CD4(+) T cells driven by allogeneic APCs. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and, moreover, attenuated the development of vasculopathy mediated by autologous peripheral blood mononuclear cells in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functional mouse and human T(regs) that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for T(reg)-based therapies.

Regenerative Medicine and Organ Transplantation: Past, Present, and Future

Transplantation. Jun, 2011  |  Pubmed ID: 21505379

This overview traces the history of regenerative medicine pertinent to organ transplantation, illustrates potential clinical applications reported to date, and highlights progress achieved in the field of complex modular organ engineering. Regenerative medicine can now produce relatively simple tissues such as skin, bladders, vessels, urethras, and upper airways, whereas engineering or generation of complex modular organs remains a major challenge. Ex vivo organ engineering may benefit from complementary investigations in the fields of developmental biology and stem cells and transplantation before its full potential can be realized.

Peripheral Blood Sampling for the Detection of Allograft Rejection: Biomarker Identification and Validation

Transplantation. Jul, 2011  |  Pubmed ID: 21494177

Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.

Immunologic Unresponsiveness to Alloantigen in Vivo: a Role for Regulatory T Cells

Immunological Reviews. May, 2011  |  Pubmed ID: 21488894

Exposure to alloantigen in vivo or in vitro induces alloantigen reactive regulatory T cells that can control transplant rejection. The mechanisms that underpin the activity of alloantigen reactive regulatory T cells in vivo are common with those of regulatory T cells that prevent autoimmunity. The identification and characterization of regulatory T cells that control rejection and contribute to the induction of immunologic unresponsiveness to alloantigens in vivo has opened up exciting opportunities for new therapies in transplantation. Findings from laboratory studies are informing the design of clinical protocols using regulatory T cells as a cellular therapy.

Pretransplant Serum CXCL9 and CXCL10 Levels Fail to Predict Acute Rejection in Kidney Transplant Recipients Receiving Induction Therapy

Transplantation. Apr, 2011  |  Pubmed ID: 21475065

Th17 Cells in Alemtuzumab-treated Patients: the Effect of Long-term Maintenance Immunosuppressive Therapy

Transplantation. Apr, 2011  |  Pubmed ID: 21412187

Leukocyte depletion at the time of transplantation with alemtuzumab (Campath-1H) has been demonstrated to be a potential strategy for reducing long-term exposure to immunosuppressive drugs. Although the impact of alemtuzumab treatment on the immune system has been explored, the effects of long-term immunosuppressive therapy in alemtuzumab-treated patients still need to be elucidated.

Th17: Contributors to Allograft Rejection and a Barrier to the Induction of Transplantation Tolerance?

Transplantation. May, 2011  |  Pubmed ID: 21378605

T helper (Th) type 17 cells are a recently described CD4 T-cell subset that may contribute to allograft rejection and act as a barrier to the induction of transplant tolerance. This review examines the involvement of Th17 cells in transplant rejection, how immunosuppressive medication may affect their induction and maintenance and the potential plasticity of developing Th17 cells. It also addresses the complex interplay between the Th17 and regulatory T-cell developmental pathways and the susceptibility of Th17 cells to regulation. Despite accumulating evidence, the precise impact of Th17 cells on transplant rejection and the induction of tolerance require further clarification.

Induction of Transplantation Tolerance Converts Potential Effector T Cells into Graft-protective Regulatory T Cells

European Journal of Immunology. Mar, 2011  |  Pubmed ID: 21243638

Naturally occurring FOXP3(+) CD4(+) Treg have a crucial role in self-tolerance. The ability to generate similar populations against alloantigens offers the possibility of preventing transplant rejection without indefinite global immunosuppression. Exposure of mice to donor alloantigens combined with anti-CD4 antibody induces operational tolerance to cardiac allografts, and generates Treg that prevent skin and islet allograft rejection in adoptive transfer models. If protocols that generate Treg in vivo are to be developed in the clinical setting it will be important to know the origin of the Treg population and the mechanisms responsible for their generation. In this study, we demonstrate that graft-protective Treg arise in vivo both from naturally occurring FOXP3(+) CD4(+) Treg and from non-regulatory FOXP3(-) CD4(+) cells. Importantly, tolerance induction also inhibits CD4(+) effector cell priming and T cells from tolerant mice have impaired effector function in vitro. Thus, adaptive tolerance induction shapes the immune response to alloantigen by converting potential effector cells into graft-protective Treg and by expanding alloreactive naturally occurring Treg. In relation to clinical tolerance induction, the data indicate that while the generation of alloreactive Treg may be critical for long-term allograft survival without chronic immunosuppression, successful protocols will also require strategies that target potential effector cells.

Immunogenicity of Embryonic Stem Cell-derived Progenitors After Transplantation

Current Opinion in Organ Transplantation. Feb, 2011  |  Pubmed ID: 21150615

This review focuses on the immunogenicity of embryonic stem cell (ESC)-derived progenitors and the impact of the immune response on applications of cell replacement therapy (CRT). Possible strategies to induce immunological tolerance to ESC-derived progenitor cells will also be discussed.

Regenerative Medicine As Applied to Solid Organ Transplantation: Current Status and Future Challenges

Transplant International : Official Journal of the European Society for Organ Transplantation. Mar, 2011  |  Pubmed ID: 21062367

In the last two decades, regenerative medicine has shown the potential for "bench-to-bedside" translational research in specific clinical settings. Progress made in cell and stem cell biology, material sciences and tissue engineering enabled researchers to develop cutting-edge technology which has lead to the creation of nonmodular tissue constructs such as skin, bladders, vessels and upper airways. In all cases, autologous cells were seeded on either artificial or natural supporting scaffolds. However, such constructs were implanted without the reconstruction of the vascular supply, and the nutrients and oxygen were supplied by diffusion from adjacent tissues. Engineering of modular organs (namely, organs organized in functioning units referred to as modules and requiring the reconstruction of the vascular supply) is more complex and challenging. Models of functioning hearts and livers have been engineered using "natural tissue" scaffolds and efforts are underway to produce kidneys, pancreata and small intestine. Creation of custom-made bioengineered organs, where the cellular component is exquisitely autologous and have an internal vascular network, will theoretically overcome the two major hurdles in transplantation, namely the shortage of organs and the toxicity deriving from lifelong immunosuppression. This review describes recent advances in the engineering of several key tissues and organs.

Regulatory T Cell Enrichment by IFN-γ Conditioning

Methods in Molecular Biology (Clifton, N.J.). 2011  |  Pubmed ID: 20941618

IFN-γ was originally characterized as a proinflammatory cytokine with T helper type 1 inducing activity, but it is now clear that it also has important immunoregulatory functions. Regulatory T cells play an important role in models of autoimmunity, GVHD, and transplantation, and offer potential as a cellular therapy. In rodent models, in vivo-generated CD25(+)CD4(+) T cells can prevent allograft rejection, but therapeutic exploitation of Treg will more likely depend on protocols that allow the generation or selection of Treg ex vivo. The experiments described in this chapter will show that alloantigen-reactive Treg can be generated/expanded ex vivo using IFN-γ, a cytokine more usually associated with allograft rejection. Although IFN-γ production has hitherto been generally regarded as nonpermissive for allograft survival, we believe this paradoxical "good-bad" role for IFN-γ may reflect an important physiological negative feedback loop.

Homing of Regulatory T Cells to Human Skin is Important for the Prevention of Alloimmune-mediated Pathology in an in Vivo Cellular Therapy Model

PloS One. 2012  |  Pubmed ID: 23300911

Regulatory T cell (Treg) therapy for immune modulation is a promising therapeutic strategy for the treatment and prevention of autoimmune disease and graft-versus-host disease (GvHD) after bone marrow transplantation. However, Treg are heterogeneous and express a variety of chemokine receptor molecules. The optimal subpopulation of Treg for therapeutic use may vary according to the pathological target. Indeed, clinical trials of Treg for the prevention of GvHD where the skin is a major target of the anti-host response have employed Treg derived from a variety of different sources. We postulated that for the effective treatment of GvHD-related skin pathology, Treg must be able to migrate to skin in order to regulate local alloimmune responses efficiently. To test the hypothesis that different populations of Treg display distinct efficacy in vivo based on their expression of tissue-specific homing molecules, we evaluated the activity of human Treg derived from two disparate sources in a model of human skin transplantation. Treg were derived from adult blood or cord blood and expanded in vitro. While Treg from both sources displayed similar in vitro suppressive efficacy, they exhibited marked differences in the expression of skin homing molecules. Importantly, only adult-derived Treg were able to prevent alloimmune-mediated human skin destruction in vivo, by virtue of their improved migration to skin. The presence of Treg within the skin was sufficient to prevent its alloimmune-mediated destruction. Additionally, Treg expressing the skin homing cutaneous lymphocyte antigen (CLA) were more efficient at preventing skin destruction than their CLA-deficient counterparts. Our findings highlight the importance of the careful selection of an effective subpopulation of Treg for clinical use according to the pathology of interest.

BIOMARKERS OF OPERATIONAL TOLERANCE IN SOLID ORGAN TRANSPLANTATION

Expert Opinion on Medical Diagnostics. Jul, 2012  |  Pubmed ID: 22988481

INTRODUCTION: Long-term immunosuppressive therapy represents a huge burden on transplant recipients, but currently cannot be omitted. Improving long-term transplant outcome by immunosuppressive drug withdrawal may be achieved in patients who have developed (partial) immunological unresponsiveness towards their graft, either spontaneously or through tolerance induction. Reliable biomarkers are essential to define such immunological unresponsiveness and will facilitate controlled immunosuppressive drug weaning as well as provide surrogate end-points for tolerance induction trials. AREAS COVERED: Tolerance biomarkers have been defined for both liver and kidney transplantation and can accurately identify operationally tolerant transplant recipients retrospectively. These two tolerance fingerprints are remarkably different, indicating the involvement of distinct mechanisms. Limited data suggest that tolerance biomarkers can be detected in immunosuppressed transplant recipients. Whether these patients can safely have their immunosuppressive drugs withdrawn needs to be established. EXPERT OPINION: Mechanistic interpretation of the kidney transplant tolerance biomarker profile dominated by B cell markers remains a challenge in light of experimental evidence suggesting the pivotal involvement of regulatory T cells. Therefore, defining animal models that resemble human transplant tolerance is crucial in understanding the underlying mechanisms. Additionally, to ensure patient safety while monitoring for tolerance, it is essential to develop biomarkers to non-invasively detect early signs of rejection as well.

Translating Tolerogenic Therapies to the Clinic - Where Do We Stand?

Frontiers in Immunology. 2012  |  Pubmed ID: 22934094

Manipulation of the immune system to prevent the development of a specific immune response is an ideal strategy to improve outcomes after transplantation. A number of experimental techniques exploiting central and peripheral tolerance mechanisms have demonstrated success, leading to the first early phase clinical trials for tolerance induction. The first major strategy centers on the facilitation of donor-cell mixed chimerism in the transplant recipient with the use of bone marrow or hematopoietic stem cell transplantation. The second strategy, utilizing peripheral regulatory mechanisms, focuses on cellular therapy with regulatory T cells. This review examines the key studies and novel research directions in the field of immunological tolerance.

Immunoregulatory Function of IL-27 and TGF-β1 in Cardiac Allograft Transplantation

Transplantation. Aug, 2012  |  Pubmed ID: 22790384

Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)-β1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4CD25 T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance.

Inflammatory Ly-6C(hi) Monocytes Play an Important Role in the Development of Severe Transplant Arteriosclerosis in Hyperlipidemic Recipients

Atherosclerosis. May, 2012  |  Pubmed ID: 22704806

Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions.

Production and Implantation of Renal Extracellular Matrix Scaffolds from Porcine Kidneys As a Platform for Renal Bioengineering Investigations

Annals of Surgery. Aug, 2012  |  Pubmed ID: 22691371

It is important to identify new sources of transplantable organs because of the critical shortage of donor organs. Tissue engineering holds the potential to address this issue through the implementation of decellularization-recellularization technology.

Regulatory Immune Cells in Transplantation

Nature Reviews. Immunology. May, 2012  |  Pubmed ID: 22627860

Immune regulation is fundamental to any immune response to ensure that it is appropriate for the perceived threat to the host. Following cell and organ transplantation, it is essential to control both the innate immune response triggered by the injured tissue and the adaptive immune response stimulated by mismatched donor and recipient histocompatibility antigens to enable the transplant to survive and function. Here, we discuss the leukocyte populations that can promote immune tolerance after cell or solid-organ transplantation. Such populations include regulatory T cells, B cells and macrophages, as well as myeloid-derived suppressor cells, dendritic cells and mesenchymal stromal cells. We consider the potential of these regulatory immune cells to develop and function in transplant recipients and their potential use as cellular therapies to promote long-term graft function.

Regenerative Medicine As Applied to General Surgery

Annals of Surgery. May, 2012  |  Pubmed ID: 22330032

The present review illustrates the state of the art of regenerative medicine (RM) as applied to surgical diseases and demonstrates that this field has the potential to address some of the unmet needs in surgery. RM is a multidisciplinary field whose purpose is to regenerate in vivo or ex vivo human cells, tissues, or organs to restore or establish normal function through exploitation of the potential to regenerate, which is intrinsic to human cells, tissues, and organs. RM uses cells and/or specially designed biomaterials to reach its goals and RM-based therapies are already in use in several clinical trials in most fields of surgery. The main challenges for investigators are threefold: Creation of an appropriate microenvironment ex vivo that is able to sustain cell physiology and function in order to generate the desired cells or body parts; identification and appropriate manipulation of cells that have the potential to generate parenchymal, stromal and vascular components on demand, both in vivo and ex vivo; and production of smart materials that are able to drive cell fate.

Laudatio to Professor Leslie Baruch Brent on the Occasion of His Honorary ESOT Membership

Transplant International : Official Journal of the European Society for Organ Transplantation. Jan, 2012  |  Pubmed ID: 22175288

Mechanisms of Rejection: Current Perspectives

Transplantation. Jan, 2012  |  Pubmed ID: 22138818

Rejection is the major barrier to successful transplantation. The immune response to an allograft is an ongoing dialogue between the innate and adaptive immune system that if left unchecked will lead to the rejection of transplanted cells, tissues, or organs. Activation of elements of the innate immune system, triggered as a consequence of tissue injury sustained during cell isolation or organ retrieval and ischemia reperfusion, will initiate and amplify the adaptive response. T cells require a minimum of two signals for activation, antigen recognition, and costimulation. The activation requirements of naive T cells are more stringent than those of memory T cells. Memory T cells are present in the majority of transplant recipients as a result of heterologous immunity. The majority of B cells require help from T cells to initiate antibody production. Antibodies reactive to donor human leukocyte antigen molecules, minor histocompatibility antigens, endothelial cells, RBCs, or autoantigens can trigger or contribute to rejection early and late after transplantation. Antibody-mediated rejection triggered by alloantibody binding and complement activation is recognized increasingly as a significant contribution to graft loss. Even though one component of the immune system may dominate and lead to rejection being described in short hand as T cell or antibody mediated, it is usually multifactorial resulting from the integration of multiple mechanisms. Identifying the molecular pathways that trigger tissue injury, signal transduction and rejection facilitates the identification of targets for the development of immunosuppressive drugs.

Single Cell Tracking of Gadolinium Labeled CD4+ T Cells by Laser Ablation Inductively Coupled Plasma Mass Spectrometry

Analytical Chemistry. Nov, 2013  |  Pubmed ID: 24080112

Cellular therapy is emerging as a promising alternative to conventional immunosuppression in the fields of hematopoietic stem cell (HSC) transplantation, autoimmune disease, and solid organ transplantation. Determining the persistence of cell-based therapies in vivo is crucial to understanding their regulatory function and requires the combination of an extremely sensitive detection technique and a stable, long-lifetime cell labeling agent. This paper reports the first application of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to perform single cell detection of T cell populations relevant to cellular immunotherapy. Purified human CD4(+) T cells were labeled with commercially available Gd-based magnetic resonance imaging (MRI) contrast agents, Omniscan and Dotarem, which enabled passive loading of up to 10(8) Gd atoms per cell. In mixed preparations of labeled and unlabeled cells, LA-ICP-MS was capable of enumerating labeled cells at close to the predicted ratio. More importantly, LA-ICP-MS single cell analysis demonstrated that the cells retained a sufficient label to remain detectable for up to 10 days post-labeling both in vitro and in vivo in an immunodeficient mouse model.

Immunomodulatory Effect of a Decellularized Skeletal Muscle Scaffold in a Discordant Xenotransplantation Model

Proceedings of the National Academy of Sciences of the United States of America. Aug, 2013  |  Pubmed ID: 23940349

Decellularized (acellular) scaffolds, composed of natural extracellular matrix, form the basis of an emerging generation of tissue-engineered organ and tissue replacements capable of transforming healthcare. Prime requirements for allogeneic, or xenogeneic, decellularized scaffolds are biocompatibility and absence of rejection. The humoral immune response to decellularized scaffolds has been well documented, but there is a lack of data on the cell-mediated immune response toward them in vitro and in vivo. Skeletal muscle scaffolds were decellularized, characterized in vitro, and xenotransplanted. The cellular immune response toward scaffolds was evaluated by immunohistochemistry and quantified stereologically. T-cell proliferation and cytokines, as assessed by flow cytometry using carboxy-fluorescein diacetate succinimidyl ester dye and cytometric bead array, formed an in vitro surrogate marker and correlate of the in vivo host immune response toward the scaffold. Decellularized scaffolds were free of major histocompatibility complex class I and II antigens and were found to exert anti-inflammatory and immunosuppressive effects, as evidenced by delayed biodegradation time in vivo; reduced sensitized T-cell proliferative activity in vitro; reduced IL-2, IFN-γ, and raised IL-10 levels in cell-culture supernatants; polarization of the macrophage response in vivo toward an M2 phenotype; and improved survival of donor-derived xenogeneic cells at 2 and 4 wk in vivo. Decellularized scaffolds polarize host responses away from a classical TH1-proinflammatory profile and appear to down-regulate T-cell xeno responses and TH1 effector function by inducing a state of peripheral T-cell hyporesponsiveness. These results have substantial implications for the future clinical application of tissue-engineered therapies.

A Shift Towards Pro-inflammatory CD16+ Monocyte Subsets with Preserved Cytokine Production Potential After Kidney Transplantation

PloS One. 2013  |  Pubmed ID: 23922945

The presence of monocyte-macrophage lineage cells in rejecting kidney transplants is associated with worse graft outcome. At present, it is still unclear how the monocyte-macrophage related responses develop after transplantation. Here, we studied the dynamics, phenotypic and functional characteristics of circulating monocytes during the first 6 months after transplantation and aimed to establish the differences between kidney transplant recipients and healthy individuals.

Ex Vivo Expanded Human Regulatory T Cells Can Prolong Survival of a Human Islet Allograft in a Humanized Mouse Model

Transplantation. Oct, 2013  |  Pubmed ID: 23917725

Human regulatory T cells (Treg) offer an attractive adjunctive therapy to reduce current reliance on lifelong, nonspecific immunosuppression after transplantation. Here, we evaluated the ability of ex vivo expanded human Treg to prevent the rejection of islets of Langerhans in a humanized mouse model and examined the mechanisms involved.

Ischemia-reperfusion Injury Accelerates Human Antibody-mediated Transplant Vasculopathy

Transplantation. Jul, 2013  |  Pubmed ID: 23856999

The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV.

A Diametric Role for OX40 in the Response of Effector/memory CD4+ T Cells and Regulatory T Cells to Alloantigen

Journal of Immunology (Baltimore, Md. : 1950). Aug, 2013  |  Pubmed ID: 23817421

OX40 is a member of the TNFR superfamily that has potent costimulatory properties. Although the impact of blockade of the OX40-OX40 ligand (OX40L) pathway has been well documented in models of autoimmune disease, its effect on the rejection of allografts is less well defined. In this article, we show that the alloantigen-mediated activation of naive and memory CD4(+) T cells results in the induction of OX40 expression and that blockade of OX40-OX40L interactions prevents skin allograft rejection mediated by either subset of T cells. Moreover, a blocking anti-OX40 had no effect on the activation and proliferation of T cells; rather, effector T cells failed to accumulate in peripheral lymph nodes and subsequently migrate to skin allografts. This was found to be the result of an enhanced degree of cell death among proliferating effector cells. In clear contrast, blockade of OX40-OX40L interactions at the time of exposure to alloantigen enhanced the ability of regulatory T cells to suppress T cell responses to alloantigen by supporting, rather than diminishing, regulatory T cell survival. These data show that OX40-OX40L signaling contributes to the evolution of the adaptive immune response to an allograft via the differential control of alloreactive effector and regulatory T cell survival. Moreover, these data serve to further highlight OX40 and OX40L as therapeutic targets to assist the induction of tolerance to allografts and self-Ags.

Cell Mediated Rejection

Methods in Molecular Biology (Clifton, N.J.). 2013  |  Pubmed ID: 23775731

Rejection is the major barrier to successful transplantation and usually results from the integration of multiple mechanisms. Activation of elements of the innate immune system, triggered as a consequence of tissue injury sustained during cell isolation or organ retrieval as well as ischemia-reperfusion, will initiate and amplify the adaptive response. For cell mediated rejection, T cells require multiple signals for activation, the minimum being two signals; antigen recognition and costimulation. The majority of B cells require help from T cells to initiate alloantibody production. Antibodies reactive to donor HLA molecules, minor histocompatibility antigens, endothelial cells, red blood cells, or autoantigens can trigger or contribute to rejection early as well as late after transplantation.

Mesenchymal Stromal Cells in Transplantation Rejection and Tolerance

Cold Spring Harbor Perspectives in Medicine. May, 2013  |  Pubmed ID: 23637312

Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell-based immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT.

Achieving Operational Tolerance in Transplantation: How Can Lessons from the Clinic Inform Research Directions?

Transplant International : Official Journal of the European Society for Organ Transplantation. Jun, 2013  |  Pubmed ID: 23517251

Since the first solid organ transplant between the Herrick twins in 1954, transplantation immunology has sought to move away from harmful immunosuppressive regimens towards tolerogenic strategies that promote long-term graft survival. This has required a concerted multinational effort with scientists and clinicians working towards a common goal. Reports of immunosuppression-free kidney and liver allograft recipients have provided the proof-of-principle, but intentional generation of tolerance in clinical transplantation is still only achieved infrequently. Recently, there have been an increasing number of encouraging developments in the field in both experimental and clinical studies. In this article, we review the latest advances in tolerance research and consider possible future barriers and solutions in achieving reliable graft acceptance in the long term.

Human IPSC-derived Mesoangioblasts, Like Their Tissue-derived Counterparts, Suppress T Cell Proliferation Through IDO- and PGE-2-dependent Pathways

F1000Research. 2013  |  Pubmed ID: 24715949

Human mesoangioblasts are currently in a phase I/II clinical trial for the treatment of patients with Duchenne muscular dystrophy. However, limitations associated with the finite life span of these cells combined with the significant numbers of mesoangioblasts required to treat all of the skeletal muscles in these patients restricts their therapeutic potential. Induced pluripotent stem cell (iPSC)-derived mesoangioblasts may provide the solution to this problem. Although, the idea of using iPSC-derived cell therapies has been proposed for quite some time, our understanding of how the immune system interacts with these cells is inadequate. Herein, we show that iPSC-derived mesoangioblasts (HIDEMs) from healthy donors and, importantly, limb-girdle muscular dystrophy 2D patients exert immunosuppressive effects on T cell proliferation.  Interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) play crucial roles in the initial activation of HIDEMs and importantly indoleamine 2,3 dioxygenase (IDO) and prostaglandin E2 (PGE-2) were identified as key mechanisms involved in HIDEM suppression of T cell proliferation. Together with recent studies confirming the myogenic function and regenerative potential of these cells, we suggest that HIDEMs could provide an unlimited alternative source for mesoangioblast-based therapies.

Multiple Unit Pooled Umbilical Cord Blood is a Viable Source of Therapeutic Regulatory T Cells

Transplantation. Jan, 2013  |  Pubmed ID: 23263503

Regulatory T cells (Treg) are potentially a useful therapeutic option for the treatment of immunopathological conditions including graft-versus-host disease. Umbilical cord blood (UCB) offers certain advantages over adult peripheral blood (APB) as a source of Treg for cellular therapy but yields far fewer Treg per unit. Pooling of Treg from multiple donors may overcome this challenge.

Ly-6C(hi) Monocytes: a Potential Target for Preventing Transplant Arteriosclerosis?

Expert Review of Clinical Immunology. Jan, 2013  |  Pubmed ID: 23256758

The Where and when of T Cell Regulation in Transplantation

Trends in Immunology. Mar, 2013  |  Pubmed ID: 23228885

Multiple cell types contribute to the peripheral regulation of T cell alloresponses in haematopoieitc cell transplantation (HCT) and solid organ transplantation (SOT). Of these, regulatory T cells (Tregs) are the principal players and have shown the greatest success in the therapeutic control of detrimental immune responses. Investigations into the induction, location, and mechanism of suppression utilised by Tregs to control alloreactive responses are ongoing. The activation and homing characteristics of Tregs are important to their regulatory capabilities, with activation and homing occurring in the same time and space as conventional T cells. This review discusses these characteristics and recent advances in the field as we move closer to the ultimate goal of utilising Tregs as treatment for allograft rejection and graft-versus-host disease (GvHD).

Conversion to Sirolimus in Kidney Transplant Recipients with Squamous Cell Cancer and Changes in Immune Phenotype

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. Feb, 2013  |  Pubmed ID: 23223314

Conversion to sirolimus from calcineurin inhibitor- (CNI), azathioprine- (AZA) and mycophenolate-based regimens reduces the risk of development of squamous cell carcinoma of the skin (SCC) in kidney transplant recipients (KTRs). Sirolimus conversion may also be protective by permitting beneficial changes in immune phenotype. It is not known how sirolimus will affect immune phenotype in KTRs with SCC.

Costimulation Blockade: Current Perspectives and Implications for Therapy

Transplantation. Feb, 2013  |  Pubmed ID: 23129000

T cells must be activated before they can elicit damage to allografts, through interaction of their T cell receptor (TCR) with peptide-MHC complex and through accessory molecules. Signaling through accessory molecules or costimulatory molecules is a critical way for the immune system to fine tune T cell activation. An emerging therapeutic strategy is to target selective molecules involved in the process of T cell activation using biologic agents, which do not impact TCR signaling, thus only manipulating the T cells, which recognize alloantigen. Costimulatory receptors and their ligands are attractive targets for this strategy and could be used both to prevent acute graft rejection as well as for maintenance immunosuppression. Therapeutic agents targeting costimulatory molecules, notably belatacept, have made the progression from the bench, through nonhuman primate studies and into the clinic. This overview describes some of the most common costimulatory molecules, their role in T cell activation, and the development of reagents, which target these pathways and their efficacy in transplantation.

Mesoangioblasts Suppress T Cell Proliferation Through IDO and PGE-2-dependent Pathways

Stem Cells and Development. Feb, 2013  |  Pubmed ID: 22913669

Human mesoangioblasts are vessel-associated stem cells that are currently in phase I/II clinical trials for the treatment of patients with Duchenne muscular dystrophy. To date, little is known about the effect of mesoangioblasts on human immune cells and vice versa. We hypothesized that mesoangioblasts could modulate the function of immune cells in a similar manner to mesenchymal stromal cells. Human mesoangioblasts did not evoke, but rather potently suppressed human T-cell proliferation and effector function in vitro in a dose- and time-dependent manner. Furthermore, mesoangioblasts exert these inhibitory effects uniformly on human CD4+ and CD8+ T cells in a reversible manner without inducing a state of anergy. Interferon (IFN)-γ and tumor necrosis factor (TNF)-α play crucial roles in the initial activation of mesoangioblasts. Indoleamine 2,3-dioxygenase (IDO) and prostaglandin E-2 (PGE) were identified as key mechanisms of action involved in the mesoangioblast suppression of T-cell proliferation. Together, these data demonstrate a previously unrecognized capacity of mesoangioblasts to modulate immune responses.

The Potential Role for Regulatory T-cell Therapy in Vascularized Composite Allograft Transplantation

Current Opinion in Organ Transplantation. Dec, 2014  |  Pubmed ID: 25333829

Vascularized composite allograft (VCA) transplantation restores defects to a degree not possible by conventional techniques. However, it is limited by the need for long-term immunosuppression and high rates of acute rejection directed against skin. There is therefore a need for a therapy that may shift the risk-benefit ratio in favour of VCA transplantation. Regulatory T cells (Tregs) are a subset of T cells with potent immunoregulatory properties and the potential to promote immunosuppression-free allograft survival. In this review, we consider the evidence for Treg therapy in VCA transplantation.

Bridging Innate with Adaptive Immunity in Transplantation: Triggers, Sensors, and Modulators

Transplantation. Nov, 2014  |  Pubmed ID: 25286058

The molecular entities present on a cell or organ transplant that trigger the innate immune response and link to the adaptive immune system are increasingly recognized as a key influence on early graft function and for determining the microenvironment that will guide longer-term graft outcomes. The 2014 Beaune Seminar in Transplant Research discussed the evidence for triggers, sensors, and modulators of innate and adaptive immunity in response to alloantigens, challenged the conventional view, developed novel hypotheses, and highlighted the potential for therapeutic manipulation of these responses.

Tolerance: One Transplant for Life

Transplantation. Jul, 2014  |  Pubmed ID: 24926829

Recently, The Transplantation Society convened a workshop to address the question, "What do we need to have in place to make tolerance induction protocols a 'standard of care' for organ transplant recipients over the next decade?" In a productive 2-day meeting, there was wide-ranging discussion on a broad series of topics, resulting in five consensus recommendations as follows: (1) establish a registry of results for patients enrolled in tolerance trials; (2) establish standardized protocols for sample collection and storage; (3) establish standardized biomarkers and assays; (4) include children 12 years and older in protocols that have been validated in adults; and (5) establish a task force to engage third-party payers in discussions of how to fund tolerance trials. Future planned workshops will focus on progress in implementing these recommendations and identifying other steps that the community needs to take.

B Cells with Immune-regulating Function in Transplantation

Nature Reviews. Nephrology. Jul, 2014  |  Pubmed ID: 24846332

In transplantation, the contribution of B cells to the rejection or acceptance of the allograft is a topic of major interest. The presence of donor-specific antibodies in transplant recipients is often associated with decreased graft function and rejection, clearly indicating a pathogenetic role of B cells in transplantation. However, data from studies in humans and rodents suggest that under certain conditions, B cells have the capacity to control or regulate the immune response to a transplanted organ. Although a great deal of attention has been focused on B cells in human and murine models of autoimmunity, our understanding of the role of these cells in transplantation is limited at present. Indeed, results in this setting are controversial and seem to depend on the model system used or the clinical situation studied. Here, we review the current understanding of the various phenotypes and roles that have been associated with immune-regulating B cells. We also discuss the mechanisms employed by subsets of these regulatory B cells to control the immune response in transplant recipients and in animal models of transplantation.

Examination of Serum MiRNA Levels in Kidney Transplant Recipients with Acute Rejection

Transplantation. Feb, 2014  |  Pubmed ID: 24531825

Induction of Transplantation Tolerance Through Regulatory Cells: from Mice to Men

Immunological Reviews. Mar, 2014  |  Pubmed ID: 24517428

Organ transplantation results in the activation of both innate and adaptive immune responses to the foreign antigens. While these responses can be limited with the use of systemic immunosuppressants, the induction of regulatory cell populations may be a novel strategy for the maintenance of specific immunological unresponsiveness that can reduce the severity of the detrimental side effects of current therapies. Our group has extensively researched different regulatory T-cell induction protocols for use as cellular therapy in transplantation. In this review, we address the cellular and molecular mechanisms behind regulatory T-cell suppression and their stability following induction protocols. We further discuss the use of different hematopoietically derived regulatory cell populations, including regulatory B cells, regulatory macrophages, tolerogenic dendritic cells, and myeloid-derived suppressor cells, for the induction of transplantation tolerance in light of new clinical trials developing therapies with some of these populations.

Predictors of Cancer Risk in the Long-term Solid-organ Transplant Recipient

Transplantation. Mar, 2014  |  Pubmed ID: 24202142

Malignancy is increasingly the leading cause of mortality in solid-organ recipients. Cancer incidence among the transplant population is overall threefold to fivefold higher than the general population with poorer outcomes for late-stage disease. Insights into the identification of patients at particular risk of developing a posttransplantation malignancy are imperative to ensure appropriate measures are instigated to reduce associated morbidity and mortality. This review focuses on potential clinical, immunologic, and genetic translational markers aimed at identifying long-term solid-organ transplant patients at high risk of developing cancer.

Mesenchymal Stromal Cells; Role in Tissue Repair, Drug Discovery and Immune Modulation

Current Drug Delivery. 2014  |  Pubmed ID: 23517624

Mesenchymal stromal cells (MSCs) participate in repair of damaged tissues, possess the potential to serve as a useful tool in the drug discovery field and exert immunosuppressive effects as demonstrated by their ability to modulate the immune response. Herein, the roles played by MSC differentiation and/or production of trophic factors involved in tissue repair are discussed. MSCs offer the opportunity to probe targets that conventional or differentiated cell lines do not express; thus providing a more refined system that allows identification of novel therapeutics. However, there are difficulties associated with drug discovery assays to which MSCs are not exempt. The immunosuppressive potential of MSCs has already been utilised in clinical trials where MSCs have been used to treat patients with graft- versus- host disease (GvHD) and autoimmune diseases. Another possible therapeutic application of MSCs lies in the field of transplantation tolerance. Although the capacity of MSCs to modulate immune responses has received much attention, the role of MSCs in transplantation tolerance is as yet unclear. In this review, we discuss the evidence for MSC induction of a state of tolerance in the transplantation setting.

Novel Biomarkers and Functional Assays to Monitor Cell-therapy-induced Tolerance in Organ Transplantation

Current Opinion in Organ Transplantation. Feb, 2015  |  Pubmed ID: 25563993

Cell-based immunotherapy offers a novel approach to minimize the need for immunosuppressive drugs and to promote a state of immunological tolerance to a transplanted organ. We review the most promising biomarkers and functional assays able to identify patients tolerant to their graft. Such a signature of tolerance is essential in the assessment of the efficacy with which trials of cellular therapies promote immunoregulation and minimize graft rejection.

Alloreactive Regulatory T cells Generated with Retinoic Acid Prevent Skin Allograft Rejection

European Journal of Immunology. Feb, 2015  |  Pubmed ID: 25381698

CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3(+) T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation.

CD45RA Distinguishes CD4+CD25+CD127-/low TSDR Demethylated Regulatory T Cell Subpopulations with Differential Stability and Susceptibility to Tacrolimus Mediated Inhibition of Suppression

Transplantation. Jul, 2016  |  Pubmed ID: 27472089

Adoptive transfer of FOXP3 regulatory T cells (Treg) offers a promising strategy to reduce damage to an allograft by the recipient's immune system. Identification of cell surface markers sufficient to purify Treg expanded ex vivo to remove cellular contaminants requires optimisation. Furthermore, the expanded Treg must be able to survive, expand and suppress in allograft recipients exposed to immunosuppressants such as tacrolimus (TAC). Reduced CD127 expression enhances identification of Treg in the human CD4CD25 population. CD45RA expression identifies naive CD4CD25 Treg with an enhanced stability of Treg phenotype.

B Cells and Antibodies in Transplantation

Transplantation. Jul, 2016  |  Pubmed ID: 26845305

Overlooked for decades, the humoral alloimmune response is increasingly recognized as a leading cause of graft loss after transplantation. However, improvement in the diagnosis of antibody-mediated rejection has not yet translated into better outcomes for transplanted patients. After an update on B cell physiology and antibody generation, the 2015 Beaune Seminar in Transplant Research challenged the conventional view of antibody-mediated rejection pathophysiology and discussed the latest promising therapeutic approaches.

Understanding Stem Cell Immunogenicity in Therapeutic Applications

Trends in Immunology. Jan, 2016  |  Pubmed ID: 26687737

Stem cells and their differentiated progeny offer great hope for treating disease by providing an unlimited source of cells for repairing or replacing damaged tissue. Initial studies suggested that, unlike 'normal' transplants, specific characteristics of stem cells enabled them to avoid immune attack. However, recent findings have revealed that the immunogenicity of stem cells may have been underestimated. Here, we review the current understanding of the mechanisms of immune recognition associated with stem cell immunogenicity, and discuss the relevance of reprogramming and differentiation strategies used to generate cells or tissue from stem cells for implantation in eliciting an immune response. We examine the effectiveness of current strategies for minimising immune attack in light of our experience in the transplantation field and, in this context, outline important challenges moving forward.

CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients

Journal of the American Society of Nephrology : JASN. May, 2016  |  Pubmed ID: 26563386

Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8(+) T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8(+) T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8(+) T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8(+) T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.

Regulatory T Cells: First Steps of Clinical Application in Solid Organ Transplantation

Transplant International : Official Journal of the European Society for Organ Transplantation. Jan, 2016  |  Pubmed ID: 25981203

Solid organ transplantation is the treatment of choice for patients with end-stage organ failure. To prevent rejection of the transplanted organ continuous treatment with immunosuppressive medication is needed. Immunosuppression may be harmful to the transplant recipient, increasing the risk of cancer, infections and cardiovascular disease. To improve transplant and patient survival, there is a need for an immune-modulatory regimen that is not only potent in preventing rejection of the transplanted organ, but has less side effects compared to current immunosuppressive regimens. Increasingly, transplantation research focusses on regulatory T cell (Treg) therapy to achieve this aim, in which Treg are used as a strategy to allow reduction of immunosuppression. Currently, the first clinical trials are underway investigating the safety and feasibility of Treg therapy in renal transplantation. This review gives an overview of the rationale of using Treg therapy in transplantation, previous experience with Treg therapy in humans, and the expected safety, potential efficacy and cost-effectiveness of Treg therapy in solid organ transplantation.

Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study

Transplantation Direct. Jan, 2017  |  Pubmed ID: 28349125

Renal transplant recipients (RTR) frequently develop complications relating to chronic immunosuppression. Identifying RTR who could safely reduce immunosuppression is therefore highly desirable. We hypothesized that "signatures" described in RTR who have stopped immunosuppression but maintained stable graft function ("operational tolerance") may enable identification of immunosuppressed RTR who are candidates for immunosuppression minimization. However, the effect of immunosuppression itself on these signatures and circulating B-cell populations is currently unknown.

CD45RA Distinguishes CD4+CD25+CD127-/low TSDR Demethylated Regulatory T Cell Subpopulations With Differential Stability and Susceptibility to Tacrolimus-Mediated Inhibition of Suppression

Transplantation. Feb, 2017  |  Pubmed ID: 28118317

Adoptive transfer of forkhead box protein (FOX)3 regulatory T (Treg) cells offers a promising strategy to reduce damage to an allograft by the recipient's immune system. Identification of cell surface markers sufficient to purify Treg cells expanded ex vivo to remove cellular contaminants requires optimization. Furthermore, the expanded Treg must be able to survive, expand, and suppress in allograft recipients exposed to immunosuppressants, such as tacrolimus (TAC). Reduced CD127 expression enhances identification of Treg in the human CD4CD25 population. CD45RA expression identifies naive CD4CD25 Treg with an enhanced stability of Treg phenotype.

How to Escape the Immune Response: What Tumours Have to Teach to Transplant Immunologists?

Transplantation. Jan, 2017  |  Pubmed ID: 28072758

Recent progress in deciphering the mechanisms underlying the concepts of tumor immunosurveillance and immunoevasion has opened new opportunities for the development of effective anti-tumor therapies. Transplant physicians and immunologists have much to learn from those direct clinical translations of basic science. The 2016 Beaune Seminar in Transplant research brought together researchers from both fields to explore and discuss significant advances in cancer biology, immunotherapies and their potential impacts for the management of cancer in transplant recipients.

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