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Other Publications (130)
- European Journal of Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- The New England Journal of Medicine
- Journal of Immunology (Baltimore, Md. : 1950)
- The Journal of Allergy and Clinical Immunology
- American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
- Current Opinion in Immunology
- The Journal of Rheumatology
- Nature Immunology
- Molecular Interventions
- The Journal of Experimental Medicine
- Nature Immunology
- Immunity
- Journal of Immunology (Baltimore, Md. : 1950)
- The Journal of Clinical Investigation
- Nature Reviews. Immunology
- Protein Engineering
- The Journal of Clinical Investigation
- American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
- Nature Medicine
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- Novartis Foundation Symposium
- Immunologic Research
- Journal of Immunology (Baltimore, Md. : 1950)
- Annual Review of Medicine
- American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
- Immunity
- The Journal of Experimental Medicine
- Journal of Immunology (Baltimore, Md. : 1950)
- Immunity
- Proceedings of the National Academy of Sciences of the United States of America
- Clinical Immunology (Orlando, Fla.)
- The Journal of Clinical Investigation
- European Journal of Immunology
- The Review of Diabetic Studies : RDS
- American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
- Annual Review of Immunology
- Nature Reviews. Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- Diabetes
- Journal of Immunology (Baltimore, Md. : 1950)
- Immunity
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- The Journal of Clinical Investigation
- Current Opinion in Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- The Journal of Experimental Medicine
- International Reviews of Immunology
- Nature Immunology
- Seminars in Immunology
- Immunity
- The Journal of Clinical Investigation
- Nature Immunology
- The Journal of Experimental Medicine
- Journal of Immunology (Baltimore, Md. : 1950)
- The Journal of Clinical Investigation
- Immunological Reviews
- Diabetes
- The Journal of Experimental Medicine
- Cell
- Proceedings of the National Academy of Sciences of the United States of America
- European Journal of Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- Clinical Immunology (Orlando, Fla.)
- Nature Reviews. Immunology
- Nature Reviews. Immunology
- Endocrinology
- Nature
- The Journal of Clinical Investigation
- Diabetes
- Nature Medicine
- Nature Immunology
- Nature Medicine
- Immunity
- Journal of Immunology (Baltimore, Md. : 1950)
- Immunological Reviews
- Journal of Clinical Immunology
- The Journal of Experimental Medicine
- Immunological Reviews
- Nature
- Proceedings of the National Academy of Sciences of the United States of America
- Diabetes
- Clinical Immunology (Orlando, Fla.)
- The Journal of Experimental Medicine
- Immunological Reviews
- Clinical Immunology (Orlando, Fla.)
- Current Opinion in Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- Endocrinology
- Nature Immunology
- Nature Immunology
- Nature Reviews. Rheumatology
- Nature Reviews. Immunology
- Immunity
- Current Opinion in Immunology
- Proceedings of the National Academy of Sciences of the United States of America
- Diabetes
- Science Translational Medicine
- Journal of Clinical Immunology
- Immunology
- Nature
- Current Opinion in Organ Transplantation
- PloS One
- Journal of Leukocyte Biology
- Journal of Leukocyte Biology
- Nature Reviews. Immunology
- Transplantation
- The Journal of Clinical Investigation
- PloS One
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- Immunological Reviews
- Immunological Reviews
- Diabetes
- The Journal of Surgical Research
- Journal of Immunology (Baltimore, Md. : 1950)
- Trends in Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- Nature
- Science Translational Medicine
- Nature Immunology
- Journal of Immunology (Baltimore, Md. : 1950)
- Journal of Immunology (Baltimore, Md. : 1950)
- The New England Journal of Medicine
- Journal of Molecular Cell Biology
Articles by Jeffrey A. Bluestone in JoVE
Other articles by Jeffrey A. Bluestone on PubMed
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The Role of CTLA-4 in Induction and Maintenance of Peripheral T Cell Tolerance
European Journal of Immunology.
Apr, 2002 |
Pubmed ID: 11920563 T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.
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The Immune Tolerance Network: a New Paradigm for Developing Tolerance-inducing Therapies
The Journal of Allergy and Clinical Immunology.
Jul, 2002 |
Pubmed ID: 12110811 Immune tolerance therapies are designed to reprogram immune cells in a highly specific fashion to eliminate pathogenic responses while preserving protective immunity. A concept that has tantalized immunologists for decades, the development of tolerance-inducing therapies, would revolutionize the management of a wide range of chronic and often debilitating diseases by obviating the need for lifelong immunosuppressive regimens. The advances of the past decade have provided a more detailed understanding of the molecular events associated with T-cell recognition and activation. Building on these advances, immunologists have demonstrated the feasibility of various tolerance-inducing approaches in small- and large-animal models of autoimmunity, allergy, and transplant graft rejection. Unprecedented opportunities to test these approaches in a variety of human diseases have now emerged. To capitalize on these advances, the National Institutes of Health recently established the Immune Tolerance Network (ITN), an international consortium of more than 70 basic and clinical immunologists dedicated to the evaluation of novel tolerance-inducing therapies and associated studies of immunologic mechanisms. By using a unique interactive approach to accelerate the development of clinical tolerance therapies, the ITN is partnering with the biotechnology and pharmaceutical industries to examine innovative tolerogenic approaches in a range of allergic and autoimmune diseases and to prevent graft rejection after transplantation. Two years since its inception, the ITN now has approximately 2 dozen clinical trials or tolerance assays studies ongoing or in later stages of protocol development. This report summarizes the rationale for emphasizing clinical research on immune tolerance and highlights the progress of the ITN.
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Activation of Human T Cells by FcR Nonbinding Anti-CD3 MAb, HOKT3gamma1(Ala-Ala)
The Journal of Clinical Investigation.
Feb, 2003 |
Pubmed ID: 12569167 Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3gamma1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.
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Clinical Trials of Transplant Tolerance: Slow but Steady Progress
American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons.
Jul, 2003 |
Pubmed ID: 12814471 The search for tolerance therapies that would thwart the alloimmune response following organ transplantation while preserving a patient's protective immune response has been a formidable goal for clinical immunologists. Over the past few decades, a more detailed understanding of the molecular events associated with T-cell recognition and activation has demonstrated the feasibility of various tolerance approaches, such as costimulation blockade, in numerous animal models of both autoimmunity and transplantation. Yet, only a few promising new therapies have reached the early stages of human clinical development. In contrast, the use of T-cell depleting induction therapy has become widespread, and new trials have been designed with immunosuppressive drug withdrawal in mind. Furthermore, nonmyeloablative mixed chimeric approaches have allowed complete immunosuppressive withdrawal in some limited cases. In the course of these investigations, however, what has become increasingly clear is that the distinctions between immunosuppression and tolerance have been blurred as the success and durability of the therapies rely as much on the state of the organ and organism as they do the mechanism of action of the drug. In this review, we provide a summary of the progress and lessons in promoting clinical transplant tolerance and an overview of promising agents.
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Transplantation of Cultured Islets from Two-layer Preserved Pancreases in Type 1 Diabetes with Anti-CD3 Antibody
American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons.
Mar, 2004 |
Pubmed ID: 14961992 We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single-donor islet transplants. Islets were isolated from two-layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C-peptide-negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti-CD3 monoclonal antibody hOKT3gamma1 (Ala-Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced-dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post-transplant. The four insulin-independent patients showed prolonged CD4+ T-cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4+CD25+ T cells. These cells suppressed the in-vitro proliferative response to donor cells and, to a lesser extent, to third-party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single-donor islet transplants.
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Therapeutic Vaccination Using CD4+CD25+ Antigen-specific Regulatory T Cells
Proceedings of the National Academy of Sciences of the United States of America.
Oct, 2004 |
Pubmed ID: 15322272 Autoimmune disease results from the dysregulation of basic tolerogenic processes designed to control self/non-self-discrimination. Approaches to treat autoimmunity have focused historically on potent immunosuppressives that block the activation and expansion of antigen-specific T cells before they differentiate into pathogenic T cell responses. These therapies are very efficient in reducing clonal expansion and altering early signaling pathways. However, once the pathogenic responses are established (i.e., autoimmunity), the interventions are less effective on activated and differentiated T cell subsets (including memory T cells) or acting in the presence of an inflammatory milieu to abort immune responses at the target tissue and systemically. Moreover, the current immunotherapies require continuous use because they do not redirect the immune system to a state of tolerance. The continuous treatment leads to long-term toxicities and can profoundly suppress protective immune responses targeted at viruses, bacteria, and other pathogens. Over the past decade, there have been tremendous advances in our understanding of the basic processes that control immune tolerance. Among the most exciting has been the identification of a professional regulatory T cell subset that has shown enormous potential in suppressing pathologic immune responses in autoimmune diseases, transplantation, and graft vs. host disease. In this review, we summarize current efforts to induce and maintain tolerance in the autoimmune diabetes setting by using therapeutic vaccination with CD4(+)CD25(+) regulatory T cells. Emphasis will be placed on approaches to exploit regulatory T cells either directly or through the use of anti-CD3 immunotherapy.
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Distinct Roles of CTLA-4 and TGF-beta in CD4+CD25+ Regulatory T Cell Function
European Journal of Immunology.
Nov, 2004 |
Pubmed ID: 15468055 Both CTLA-4 and TGF-beta have been implicated in suppression by CD4+CD25+ regulatory T cells (Treg). In this study, the relationship between CTLA-4 and TGF-beta in Treg function was examined. Blocking CTLA-4 on wild-type Treg abrogated their suppressive activity in vitro, whereas neutralizing TGF-beta had no effect, supporting a TGF-beta-independent role for CTLA-4 in Treg-mediated suppression in vitro. In CTLA-4-deficient mice, Treg development and homeostasis was normal. Moreover, Treg from CTLA-4-deficient mice exhibited uncompromised suppressive activity in vitro. These CTLA-4-deficient Treg expressed increased levels of the suppressive cytokines IL-10 and TGF-beta, and in vitro suppression mediated by CTLA-4(-/-) Treg was markedly reduced by neutralizing TGF-beta, suggesting that CTLA-4-deficient Treg develop a compensatory suppressive mechanism through CTLA-4-independent production of TGF-beta. Together, these data suggest that CTLA-4 regulates Treg function by two distinct mechanisms, one during functional development of Treg and the other during the effector phase, when the CTLA-4 signaling pathway is required for suppression. These results help explain contradictions in the literature and support the existence of functionally distinct Treg.
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Treatment with Nonmitogenic Anti-CD3 Monoclonal Antibody Induces CD4+ T Cell Unresponsiveness and Functional Reversal of Established Experimental Autoimmune Encephalomyelitis
Journal of Immunology (Baltimore, Md. : 1950).
Apr, 2005 |
Pubmed ID: 15814673 In vivo administration of anti-CD3 Ab induces both immune tolerance and undesirable side-effects resulting from nonspecific proinflammatory cytokine production. In the current study, we investigated the therapeutic potential of two structurally altered forms of the anti-CD3 Ab in ameliorating established experimental autoimmune encephalomyelitis. Administration of either a chimeric (NM-IgG3) or digestion product (NM-F(ab')2) form of the anti-CD3 Ab during established experimental autoimmune encephalomyelitis conferred significant protection from clinical disease progression and was associated with decreased Ag-specific T cell proliferation, cytokine production, and CNS inflammation. Interestingly, while this protection correlated with an increase in the frequency of CD4(+)CD25(+) regulatory T cells, neither prior depletion of regulatory T cells nor anti-TGF-beta treatment abrogated the treatment's efficacy. Importantly, both treatments induced normal levels of intracellular Ca(2+)-flux, but significantly diminished levels of TCR signaling. Consequent to this decreased level of TCR-mediated signaling were alterations in the level of apoptosis and CD4+ T cell trafficking resulting in a profound lymphopenia. Collectively, these results indicate that nonmitogenic anti-CD3 directly induces a state of immune unresponsiveness in primed pathogenic autoreactive effector cells via mechanisms that may involve the induction of T cell tolerance, apoptosis, and/or alterations in cell trafficking.
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An Important Role of CD80/CD86-CTLA-4 Signaling During Photocarcinogenesis in Mice
Journal of Immunology (Baltimore, Md. : 1950).
May, 2005 |
Pubmed ID: 15843526 Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86(-/-) mice produced skin cancer earlier compared with CD80(-/-) and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80(-/-)/CD86(-/-) mice had strongly reduced numbers of UV-induced CD4(+)CD25(+) suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4(+)CD25(+) T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.
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A Single Course of Anti-CD3 Monoclonal Antibody HOKT3gamma1(Ala-Ala) Results in Improvement in C-peptide Responses and Clinical Parameters for at Least 2 Years After Onset of Type 1 Diabetes
Diabetes.
Jun, 2005 |
Pubmed ID: 15919798 Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3gamma1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 +/- 9.6% of response at study entry in drug-treated patients vs. 53 +/- 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA(1c) and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8(+) T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.
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A Comprehensive Review of Interventions in the NOD Mouse and Implications for Translation
Immunity.
Aug, 2005 |
Pubmed ID: 16111631 Type 1 diabetes (T1D) animal models such as the nonobese diabetic (NOD) mouse have improved our understanding of disease pathophysiology, but many candidate therapeutics identified therein have failed to prevent/cure human disease. We have performed a comprehensive evaluation of disease-modifying agents tested in the NOD mouse based on treatment timing, duration, study length, and efficacy. Interestingly, some popular tenets regarding NOD interventions were not confirmed: all treatments do not prevent disease, treatment dose and timing strongly influence efficacy, and several therapies have successfully treated overtly diabetic mice. The analysis provides a unique perspective on NOD interventions and suggests that the response of this model to therapeutic interventions can be a useful predictor of the human response as long as careful consideration is given to treatment dose, timing, and protocols; more thorough investigation of these parameters should improve clinical translation.
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Expansion of Functional Endogenous Antigen-specific CD4+CD25+ Regulatory T Cells from Nonobese Diabetic Mice
Journal of Immunology (Baltimore, Md. : 1950).
Sep, 2005 |
Pubmed ID: 16116193 CD4+CD25+Foxp3+ regulatory T cells (T(reg)) are critical for controlling autoimmunity. Evidence suggests that T(reg) development, peripheral maintenance, and suppressive function are dependent on Ag specificity. However, there is little direct evidence that the T(reg) responsible for controlling autoimmunity in NOD mice or other natural settings are Ag specific. In fact, some investigators have argued that polyclonal Ag-nonspecific T(reg) are efficient regulators of immunity. Thus, the goal of this study was to identify, expand, and characterize islet Ag-specific T(reg) in NOD mice. Ag-specific T(reg) from NOD mice were efficiently expanded in vitro using IL-2 and beads coated with recombinant islet peptide mimic-MHC class II and anti-CD28 mAb. The expanded Ag-specific T(reg) expressed prototypic surface markers and cytokines. Although activated in an Ag-specific fashion, the expanded T(reg) were capable of bystander suppression both in vitro and in vivo. Importantly, the islet peptide mimic-specific T(reg) were more efficient than polyclonal T(reg) in suppressing autoimmune diabetes. These results provide a direct demonstration of the presence of autoantigen-specific T(reg) in the natural setting that can be applied as therapeutics for organ-specific autoimmunity.
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A Peptide of Glutamic Acid Decarboxylase 65 Can Recruit and Expand a Diabetogenic T Cell Clone, BDC2.5, in the Pancreas
Journal of Immunology (Baltimore, Md. : 1950).
Sep, 2005 |
Pubmed ID: 16148106 Self peptide-MHC ligands create and maintain the mature T cell repertoire by positive selection in the thymus and by homeostatic proliferation in the periphery. A low affinity/avidity interaction among T cells, self peptides, and MHC molecules has been suggested for these events, but it remains unknown whether or how this self-interaction is involved in tolerance and/or autoimmunity. Several lines of evidence implicate the glutamic acid decarboxylase 65 (GAD-65) peptide, p524-543, as a specific, possibly low affinity, stimulus for the spontaneously arising, diabetogenic T cell clone BDC2.5. Interestingly, BDC2.5 T cells, which normally are unresponsive to p524-543 stimulation, react to the peptide when provided with splenic APC obtained from mice immunized with the same peptide, p524-543, but not, for example, with hen egg white lysozyme. Immunization with p524-543 increases the susceptibility of the NOD mice to type 1 diabetes induced by the adoptive transfer of BDC2.5 T cells. In addition, very few CFSE-labeled BDC2.5 T cells divide in the recipient's pancreas after transfer into a transgenic mouse that overexpresses GAD-65 in B cells, whereas they divide vigorously in the pancreas of normal NOD recipients. A special relationship between the BDC2.5 clone and the GAD-65 molecule is further demonstrated by generation of a double-transgenic mouse line carrying both the BDC2.5 TCR and GAD-65 transgenes, in which a significant reduction of BDC2.5 cells in the pancreas has been observed, presumably due to tolerance induction. These data suggest that unique and/or altered processing of self Ags may play an essential role in the development and expansion of autoreactive T cells.
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CD127 Expression Inversely Correlates with FoxP3 and Suppressive Function of Human CD4+ T Reg Cells
The Journal of Experimental Medicine.
Jul, 2006 |
Pubmed ID: 16818678 Regulatory T (T reg) cells are critical regulators of immune tolerance. Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4(+) T cells in peripheral blood. We demonstrate that the majority of these cells are FoxP3(+), including those that express low levels or no CD25. A combination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accounting for significantly more cells that previously identified based on other cell surface markers. These cells were highly suppressive in functional suppressor assays. In fact, cells separated based solely on CD4 and CD127 expression were anergic and, although representing at least three times the number of cells (including both CD25(+)CD4(+) and CD25(-)CD4(+) T cell subsets), were as suppressive as the "classic" CD4(+)CD25(hi) T reg cell subset. Finally, we show that CD127 can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.
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Inhibition of T Cell Activation and Autoimmune Diabetes Using a B Cell Surface-linked CTLA-4 Agonist
The Journal of Clinical Investigation.
Aug, 2006 |
Pubmed ID: 16886063 CTL-associated antigen 4 (CTLA-4) engagement negatively regulates T cell activation and function and promotes immune tolerance. However, it has been difficult to explore the biology of selective engagement of CTLA-4 in vivo because CTLA-4 shares its ligands, B7-1 and B7-2, with CD28. To address this issue, we developed a Tg mouse expressing a single-chain, membrane-bound anti-CTLA-4 Ab (scFv) on B cells. B and T cells developed normally and exhibited normal phenotype in the steady state and after activation in these mice. However, B cells from scFv Tg+ mice (scalphaCTLA4+) prevented T cell proliferation and cytokine production in mixed lymphocyte reactions. Additionally, mice treated with scalphaCTLA4+ B cells had decreased T cell-dependent B cell Ab production and class switching in vivo after antigen challenge. Furthermore, expression of this CTLA-4 agonist protected NOD mice from spontaneous autoimmune diabetes. Finally, this disease prevention occurred in Treg-deficient NOD.B7-1/B7-2 double-knockout mice, suggesting that the effect of the CTLA-4 agonist directly attenuates autoreactive T cell activation, not Treg activation. Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance.
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Regulatory T-cell Physiology and Application to Treat Autoimmunity
Immunological Reviews.
Aug, 2006 |
Pubmed ID: 16903917 Endowed with the ability to actively suppress an immune response, regulatory T cells (Tregs) hold the promise of halting ongoing pathogenic autoimmunity and restoring self-tolerance in patients suffering from autoimmune diseases. Through many in vitro and in vivo studies, we have learned that Tregs can function in the lymph nodes as well as in the peripheral tissues. In vivo, Tregs act through dendritic cells to limit autoreactive T-cell activation, thus preventing their differentiation and acquisition of effector functions. By limiting the supply of activated pathogenic cells, Tregs prevent or slow down the progression of autoimmune diseases. However, this protective mechanism appears insufficient in autoimmune individuals, likely because of a shortage of Tregs cells and/or the development and accumulation of Treg-resistant pathogenic T cells over the long disease course. Thus, restoration of self-tolerance in these patients will likely require purging of pathogenic T cells along with infusion of Tregs with increased ability to control ongoing tissue injury. In this review, we highlight advances in dissecting Treg function in vivo in autoimmune settings and summarize multiple studies that have overcome the limitations of the low abundance of Tregs and their hypoproliferative phenotype to develop Treg-based therapies.
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Analysis of T-cell Assays to Measure Autoimmune Responses in Subjects with Type 1 Diabetes: Results of a Blinded Controlled Study
Diabetes.
Sep, 2006 |
Pubmed ID: 16936208 Type 1 diabetes is a chronic autoimmune disease mediated by autoreactive T-cells. Several experimental therapies targeting T-cells are in clinical trials. To understand how these therapies affect T-cell responses in vivo, assays that directly measure human T-cell function are needed. In a blinded, multicenter, case-controlled study conducted by the Immune Tolerance Network, we tested responses in an immunoblot and T-cell proliferative assay to distinguish type 1 diabetic patients from healthy control subjects. Peripheral blood cells from 39 healthy control subjects selected for DR4 and 23 subjects with recently diagnosed type 1 diabetes were studied. Autoantibody responses were measured in serum samples. Positive responses in both assays were more common in peripheral blood mononuclear cells from new-onset type 1 diabetic patients compared with control subjects. The proliferative, immunoblot, and autoantibody assays had sensitivities of 58, 91, and 78% with specificities of 94, 83, and 85%, respectively. When cellular assays were combined with autoantibody measurements, the sensitivity of the measurements was 75% with 100% specificity. We conclude that cellular assays performed on peripheral blood have a high degree of accuracy in discriminating responses in subjects with type 1 diabetes from healthy control subjects. They may be useful for assessment of cellular autoimmune responses involved in type 1 diabetes.
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Insulin-induced Remission in New-onset NOD Mice is Maintained by the PD-1-PD-L1 Pathway
The Journal of Experimental Medicine.
Nov, 2006 |
Pubmed ID: 17116737 The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)-programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte-associated antigen 4 pathway. Anti-PD-1 and anti-PD-L1, but not anti-PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1-PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1-PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1-PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.
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Adaptive TGF-beta-dependent Regulatory T Cells Control Autoimmune Diabetes and Are a Privileged Target of Anti-CD3 Antibody Treatment
Proceedings of the National Academy of Sciences of the United States of America.
Apr, 2007 |
Pubmed ID: 17389382 Previous results have shown that CD4(+)CD25(+) regulatory T cells (Tregs) control autoimmunity in a spontaneous model of type 1 diabetes, the nonobese diabetic (NOD) mouse. Moreover, anti-CD3 reverses diabetes in this setting by promoting Tregs that function in a TGF-beta-dependent manner. This finding contrasts with a large body of work suggesting that CD4(+)CD25(high) Tregs act in a cytokine-independent manner, thus suggesting that another type of Treg is operational in this setting. We sought to determine the basis of suppression both in untreated NOD mice and in those treated with anti-CD3. Our present results show that a subset of foxP3(+) cells present within a CD4(+)CD25(low) lymphocyte subset suppresses T cell immunity in spontaneously diabetic NOD mice in a TGF-beta-dependent manner, a functional property typical of "adaptive" regulatory T cells. This distinct Treg subset is evident in NOD, but not normal, mice, suggesting that the NOD mice may generate these adaptive Tregs in an attempt to regulate ongoing autoimmunity. Importantly, in two distinct in vivo models, these TGF-beta-dependent adaptive CD4(+)CD25(low) T cells can be induced from peripheral CD4(+)CD25(-) T lymphocytes by anti-CD3 immunotherapy which correlates with the restoration of self-tolerance.
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Selective MiRNA Disruption in T Reg Cells Leads to Uncontrolled Autoimmunity
The Journal of Experimental Medicine.
Sep, 2008 |
Pubmed ID: 18725525 A new regulatory T (T reg) cell-specific, FoxP3-GFP-hCre bacterial artificial chromosome transgenic mouse was crossed to a conditional Dicer knockout (KO) mouse strain to analyze the role of microRNAs (miRNAs) in the development and function of T reg cells. Although thymic T reg cells developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient T reg lineage cells failed to remain stable, as a subset of cells down-regulated the T reg cell-specific transcription factor FoxP3, whereas the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4) associated with the T reg cell fingerprint. In fact, a significant percentage of the T reg lineage cells took on a T helper cell memory phenotype including increased levels of CD127, interleukin 4, and interferon gamma. Importantly, Dicer-deficient T reg cells lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 KO phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated T reg cell function in vivo and homeostasis of the adaptive immune system.
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Control of Peripheral T-cell Tolerance and Autoimmunity Via the CTLA-4 and PD-1 Pathways
Immunological Reviews.
Aug, 2008 |
Pubmed ID: 18759926 Classically, the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and B7 families of cell surface molecules regulate complex signaling pathways that profoundly affect T-cell responses. The recent identification and characterization of additional CD28 and B7 family members including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1) (B7-H1), and PD-L2 (B7-DC) has added to the complexity and greater appreciation of how surface molecules control T-cell activation and peripheral tolerance. CD28/B7 interactions mediate co-stimulation and significantly enhance peripheral T-cell responses. CTLA-4, in contrast, interacting with the same B7 molecules, results in decreased T-lymphocyte activity and regulates the immune response. Similarly, PD-1 interactions with PD-L1 and PD-L2 downmodulate T-cell immune responses. Despite these similarities, the regulatory roles of the CTLA-4 and PD-1 pathways are distinct. This may be due, at least in part, to the differential expression patterns of the CTLA-4 and PD-1 ligands both temporally and spatially. This article examines the role of CTLA-4 and PD-1 in limiting autoreactivity and establishing peripheral self-tolerance with the hypothesis that CTLA-4 signals are required early in the lymph node during initiation of an immune response and PD-1 pathways act late at the tissue sites to limit T-cell activity.
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Tyrosine Kinase Inhibitors Reverse Type 1 Diabetes in Nonobese Diabetic Mice
Proceedings of the National Academy of Sciences of the United States of America.
Dec, 2008 |
Pubmed ID: 19015530 The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRbetaIg, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.
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Regulating the Regulators: Costimulatory Signals Control the Homeostasis and Function of Regulatory T Cells
Immunological Reviews.
May, 2009 |
Pubmed ID: 19426214 SUMMARY: Costimulation is a concept that goes back to the early 1980s when Lafferty and others hypothesized that cell surface and soluble molecules must exist that are essential for initiating immune responses subsequent to antigen exposure. The explosion in this field of research ensued as over a dozen molecules have been identified to function as second signals following T-cell receptor engagement. By 1994, it seemed clear that the most prominent costimulatory pathway CD28 and functionally related costimulatory molecules, such as CD154, were the major drivers of a positive immune response. Then the immunology world turned upside down. CD28 knockout mice, which were, in most cases, immunodeficient, led to increased autoimmunity when bred into the non-obese diabetic background. Another CD28 family member, cytotoxic T-lymphocyte-associated protein 4, which was presumed to be a costimulatory molecule on activated T cells, turned out to be critical in downregulating immunity. These results, coupled with the vast suppressor cell literature which had been largely rebuked, suggested that the immune system was not poised for response but controlled in such a way that regulation was dominant. Over the last decade, we have learned that these costimulatory molecules play a key role in the now classical CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) that provide critical control of unwanted autoimmune responses. In this review, we discuss the connections between costimulation and Tregs that have changed the costimulation paradigm.
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T-bet-deficient NOD Mice Are Protected from Diabetes Due to Defects in Both T Cell and Innate Immune System Function
Journal of Immunology (Baltimore, Md. : 1950).
Jul, 2009 |
Pubmed ID: 19535634 The transcription factor T-bet (Tbx21) is critical for Th1 polarization of CD4(+) T cells. Genetic deletion of Tbx21 can cause either exacerbation or attenuation of different autoimmune diseases in animal models. In the nonobese diabetic (NOD) mouse, genetic deletion of the Ifng or the Il12b (IL-12p40) genes, which are both critical Th1 cytokines, does not reduce the incidence of autoimmune diabetes. These results suggest that autoimmune diabetes in the NOD may not be a Th1-driven disease. However, we report that Tbx21 deficiency in the NOD mouse completely blocks insulitis and diabetes due to defects both in the initiation of the anti-islet immune response and in the function of CD4(+) effector T cells. We find defective priming of naive islet-reactive T cells by the innate immune system in Tbx21(-/-) animals. By contrast to naive cells, activated islet-reactive BDC2.5 TCR-transgenic T cells do not require Tbx21 in recipient animals for efficient adoptive transfer of diabetes. However, when these BDC2.5 TCR-transgenic effector cells lack Tbx21, they are less effective at entering the pancreas and promoting diabetes than Tbx21(+/+) cells. Tbx21(-/-) regulatory T cells function normally in vitro and diabetes can be restored in Tbx21(-/-) mice by reducing regulatory T cell numbers. Thus, the absence of diabetes in the NOD.Tbx21(-/-) is due to intrinsic defects in both T cells and cells of the innate immune system paired with the relative preservation of regulatory T cell function.
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Lethal Effect of CD3-specific Antibody in Mice Deficient in TGF-beta1 by Uncontrolled Flu-like Syndrome
Journal of Immunology (Baltimore, Md. : 1950).
Jul, 2009 |
Pubmed ID: 19561097 CD3-specific Ab therapy results in a transient, self-limiting, cytokine-associated, flu-like syndrome in experimental animals and in patients, but the underlying mechanism for this spontaneous resolution remains elusive. By using an in vivo model of CD3-specific Ab-induced flu-like syndrome, we show in this paper that a single injection of sublethal dose of the Ab killed all TGF-beta1(-/-) mice. The death of TGF-beta1(-/-) mice was associated with occurrence of this uncontrolled flu-like syndrome, as demonstrated by a sustained storm of systemic inflammatory TNF and IFN-gamma cytokines. We present evidence that deficiency of professional phagocytes to produce TGF-beta1 after apoptotic T cell clearance may be responsible, together with hypersensitivity of T cells to both activation and apoptosis, for the uncontrolled inflammation. These findings indicate a key role for TGF-beta1 and phagocytes in protecting the recipients from lethal inflammation and resolving the flu-like syndrome after CD3-specific Ab treatment. The study may also provide a novel molecular mechanism explaining the early death in TGF-beta1(-/-) mice.
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Insulin Receptor Substrate-2 in Beta-cells Decreases Diabetes in Nonobese Diabetic Mice
Endocrinology.
Oct, 2009 |
Pubmed ID: 19574401 Insulin receptor substrate-2 (Irs2) integrates insulin-like signals with glucose and cAMP agonists to regulate beta-cell growth, function, and survival. This study investigated whether increased Irs2 concentration in beta-cells could reduce beta-cell destruction and the incidence of type 1 diabetes in nonobese diabetic (NOD) mice. NOD mice were intercrossed with C57BL/6 mice overexpressing Irs2 specifically in beta-cells to create NOD(Irs2) mice. After backcrossing NOD(Irs2) mice for 12 generations, glucose homeostasis and diabetes incidence were compared against NOD littermates. Compared with 12-wk-old NOD mice, the progression of severe insulitis was reduced and islet mass was increased in NOD(Irs2) mice. Moreover, the risk of diabetes decreased 50% in NOD(Irs2) mice until the experiment was terminated at 40 wk of age. Nondiabetic NOD(Irs2) mice displayed better glucose tolerance than nondiabetic NOD mice throughout the duration of the study and up to the age of 18 months. The effect of Irs2 to increase islet mass and improve glucose tolerance raised the possibility that NOD(Irs2) mice might have an increased capacity to respond to anti-CD3 antibody, which can induce remission of overt diabetes in some NOD mice. Anti-CD3 antibody injections restored glucose tolerance in newly diabetic NOD and NOD(Irs2) mice; however, anti-CD3-treated NOD(Irs2) mice were less likely than NOD mice to relapse during the experimental period because they displayed 10-fold greater beta-cell mass and mitogenesis. In conclusion, increased Irs2 attenuated the progression of beta-cell destruction, promoted beta-cell mitogenesis, and reduced diabetes incidence in NOD(Irs2) mice.
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The Functional Plasticity of T Cell Subsets
Nature Reviews. Immunology.
Nov, 2009 |
Pubmed ID: 19809471 In 1986, Robert Coffman and Timothy Mossman first described the division of CD4(+) T cells into functional subsets, termed T helper 1 (T(H)1) and T(H)2, based on cytokine production, and in doing so unwittingly opened a Pandora's box of complexity and controversy. Although the mechanisms that regulate T(H)1 and T(H)2 cells are now well known, recent descriptions of other CD4(+) T cell subsets--such as regulatory T cells, T follicular helper cells, T(H)17, T(H)22 and most recently T(H)9 and T(H)22 cells--have questioned how we think of T cell subsets and what commitment to a functional T cell subset means. Here, Nature Reviews Immunology asks four leaders in the field their thoughts on the functional plasticity of T cell subsets.
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Suppression of Human Anti-porcine Natural Killer Cell Xenogeneic Responses by Combinations of Monoclonal Antibodies Specific to CD2 and NKG2D and Extracellular Signal-regulated Kinase Kinase Inhibitor
Immunology.
Aug, 2010 |
Pubmed ID: 20406306 Natural killer (NK) cells can destroy xenogeneic tissues by antibody-dependent cell cytotoxicity (ADCC) and direct lysis. Unlike ADCC, activating interactions between human NK receptors and their cognate ligands in pigs are not fully elucidated. We set up this study to identify human NK activating receptors recognizing porcine cells isolated from distinct organs, e.g., aorta, cornea and liver, and to provide a molecular basis for effective immunosuppressive regimens. Among the array of NK receptors tested, NKp46, 2B4, CD49d, CD48, CD2 and NKG2D, only CD2 and NKG2D were shown to be involved in both cytotoxicity and cytokine (interferon-gamma and tumour necrosis factor-alpha) production against porcine targets. Simultaneous blocking of CD2 and NKG2D by combining its monoclonal antibodies further suppressed xenogeneic NK responses. Moreover, addition of a suboptimal dose of PD98059, an extracellular signal-regulated kinase (ERK) kinase inhibitor, to those cells maximally reduced NK cytotoxicity, suggesting that ERK plays an important role in NK-mediated xenoreactivity. These impairments in NK cells were tightly associated with defective intracellular calcium mobilization and the subsequent degranulation process. Therefore, our data demonstrate a distinct role of CD2 and NKG2D on human NK cells in recognizing porcine grafts and further provide a potentially efficacious combinational regimen using anti-CD2 and anti-NKG2D monoclonal antibodies with PD98059 in a pig-to-human transplantation model.
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FK506 Causes Cellular and Functional Defects in Human Natural Killer Cells
Journal of Leukocyte Biology.
Dec, 2010 |
Pubmed ID: 20671192 The role of NK cells in allogeneic HCT has been increasingly appreciated, particularly in the GVL effect. Although FK506 has been used widely to prevent GVHD, its action was considered to be primarily through activated T cells. In this study, we provide direct evidence for the first time that human NK cells are immediate targets of FK506. Our in vivo data from patients undergoing peripheral blood stem cell transplantation or BMT showed a reduced number of NK cells with down-regulated CD25 expression in their peripheral blood compartment. Likewise, FK506 caused profound inhibition of NK cell proliferation in vitro and suppressed NK cytotoxicity and cytokine secretion in response to IL-2. These defects were accompanied by impaired cell clustering and selective down-regulation of adhesion molecules, ICAM-1, CD2, CD49d, and CD58. Furthermore, FK506 specifically inhibited expression of NKG2D, CD48, and DNAM1 receptors without affecting that of 2B4, NKp30, NKp44, and NKp46. As a result, natural cytotoxicity against K562 tumor targets was impaired, while leaving redirected ADCC via 2B4 intact. Finally, FK506-treated NK cells showed impaired IL-2R signaling and inhibition of STAT3. Collectively, these signaling impairments and selective down-regulation of NK receptors by FK506 may underlie the proliferative and functional defects of NK cells. Thus, our data provide a new insight into the mechanism of immunosuppression by FK506, which should be considered to interpret the outcome of graft transplantation.
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Clusterin Synergizes with IL-2 for the Expansion and IFN-γ Production of Natural Killer Cells
Journal of Leukocyte Biology.
Nov, 2010 |
Pubmed ID: 20729304 CLU is a secreted, multifunctional protein implicated in several immunologic and pathologic conditions. As the level of serum CLU was shown to be elevated during inflammatory responses, we questioned if CLU might interact with circulating lymphocytes leading to functional consequences. To assess this possibility directly, mouse splenocytes and purified NK cells were cultured with varying dose of CLU, and its effect on cell proliferation was examined. Our data showed that CLU up-regulated DNA synthesis and expansion of NK cells significantly in response to a suboptimal, but not maximal, dose of IL-2, and CLU alone did not exhibit such effects. This CLU-mediated synergy required the co-presence of CLU at the onset of IL-2 stimulation and needed a continuous presence during the rest of the culture. Importantly, NK cells stimulated with CLU showed increased formation of cell clusters and a CD69 activation receptor, representing a higher cellular activation status compared with those from the control group. Furthermore, these NK cells displayed elevated IFN-γ production upon RMA/S tumor target exposures, implying that CLU regulates not only NK cell expansion but also effector function of NK cells. Collectively, our data present a previously unrecognized function of CLU as a novel regulator of NK cells via providing costimulation required for cell proliferation and IFN-γ secretion. Therefore, the role of CLU on NK cells should be taken into consideration for the previously observed, diverse functions of CLU in chronic inflammatory and autoimmune conditions.
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Expression of αvβ8 Integrin on Dendritic Cells Regulates Th17 Cell Development and Experimental Autoimmune Encephalomyelitis in Mice
The Journal of Clinical Investigation.
Dec, 2010 |
Pubmed ID: 21099117 Th17 cells promote a variety of autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TGF-β is required for conversion of naive T cells to Th17 cells, but the mechanisms regulating this process are unknown. Integrin αvβ8 on DCs can activate TGF-β, and this process contributes to the development of induced Tregs. Here, we have now shown that integrin αvβ8 expression on DCs plays a critical role in the differentiation of Th17 cells. Th17 cells were nearly absent in the colons of mice lacking αvβ8 expression on DCs. In addition, these mice and the DCs harvested from them had an impaired ability to convert naive T cells into Th17 cells in vivo and in vitro, respectively. Importantly, mice lacking αvβ8 on DCs showed near-complete protection from experimental autoimmune encephalomyelitis. Our results therefore suggest that the integrin αvβ8 pathway is biologically important and that αvβ8 expression on DCs could be a therapeutic target for the treatment of Th17-driven autoimmune disease.
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Plasticity of Human Regulatory T Cells in Healthy Subjects and Patients with Type 1 Diabetes
Journal of Immunology (Baltimore, Md. : 1950).
Apr, 2011 |
Pubmed ID: 21368230 Regulatory T cells (Tregs) constitute an attractive therapeutic target given their essential role in controlling autoimmunity. However, recent animal studies provide evidence for functional heterogeneity and lineage plasticity within the Treg compartment. To understand better the plasticity of human Tregs in the context of type 1 diabetes, we characterized an IFN-γ-competent subset of human CD4(+)CD127(lo/-)CD25(+) Tregs. We measured the frequency of Tregs in the peripheral blood of patients with type 1 diabetes by epigenetic analysis of the Treg-specific demethylated region (TSDR) and the frequency of the IFN-γ(+) subset by flow cytometry. Purified IFN-γ(+) Tregs were assessed for suppressive function, degree of TSDR demethylation, and expression of Treg lineage markers FOXP3 and Helios. The frequency of Tregs in peripheral blood was comparable but the FOXP3(+)IFN-γ(+) fraction was significantly increased in patients with type 1 diabetes compared to healthy controls. Purified IFN-γ(+) Tregs expressed FOXP3 and possessed suppressive activity but lacked Helios expression and were predominately methylated at the TSDR, characteristics of an adaptive Treg. Naive Tregs were capable of upregulating expression of Th1-associated T-bet, CXCR3, and IFN-γ in response to IL-12. Notably, naive, thymic-derived natural Tregs also demonstrated the capacity for Th1 differentiation without concomitant loss of Helios expression or TSDR demethylation.
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Intrinsic and Extrinsic Control of Peripheral T-cell Tolerance by Costimulatory Molecules of the CD28/ B7 Family
Immunological Reviews.
May, 2011 |
Pubmed ID: 21488898 Positive and negative costimulation by members of the CD28 family is critical for the development of productive immune responses against foreign pathogens and their proper termination to prevent inflammation-induced tissue damage. In addition, costimulatory signals are critical for the establishment and maintenance of peripheral tolerance. This paradigm has been established in many animal models and has led to the development of immunotherapies targeting costimulation pathways for the treatment of cancer, autoimmune disease, and allograft rejection. During the last decade, the complexity of the biology of costimulatory pathways has greatly increased due to the realization that costimulation does not affect only effector T cells but also influences regulatory T cells and antigen-presenting cells. Thus, costimulation controls T-cell tolerance through both intrinsic and extrinsic pathways. In this review, we discuss the influence of costimulation on intrinsic and extrinsic pathways of peripheral tolerance, with emphasis on members of the CD28 family, CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1), as well as the downstream cytokine interleukin-1 (IL-2).
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Anti-CD3 Therapy Promotes Tolerance by Selectively Depleting Pathogenic Cells While Preserving Regulatory T Cells
Journal of Immunology (Baltimore, Md. : 1950).
Aug, 2011 |
Pubmed ID: 21742976 Monoclonal anti-CD3 Abs have been used clinically for two decades to reverse steroid-resistant acute graft rejection. In autoimmune diabetes, short course treatment with FcR-nonbinding (FNB) anti-CD3 mAb in mice with recent onset of diabetes induces long-term disease remission. Induction of tolerogenic regulatory T cells (Tregs) has been implicated to be one of the mechanisms of action by FNB anti-CD3 mAb in these settings. In this study, we examined the effect of FNB anti-CD3 mAb treatment on the homeostasis of naive, effector, and regulatory T cells in vivo. Anti-CD3 treatment induced a transient systemic rise in the percentage but not absolute number of CD4(+)Foxp3(+) Tregs due to selective depletion of CD4(+)Foxp3(-) conventional T cells. T cell depletion induced by FNB anti-CD3 mAb was independent of the proapoptotic proteins Fas, caspase-3, and Bim and was not inhibited by overexpression of the anti-apoptotic protein, Bcl-2. Tregs were not preferentially expanded and we found no evidence of conversion of conventional T cells into Tregs, suggesting that the pre-existing Tregs are resistant to anti-CD3-induced cell death. Interestingly, expression of the transcription factor Helios, which is expressed by thymus-derived natural Tregs, was increased in Tregs after FNB anti-CD3 mAb treatment, suggesting that the anti-CD3 treatment can alter, and potentially stabilize, Treg function. Taken together, the results suggest that FNB anti-CD3 therapy promotes tolerance by restoring the balance between pathogenic and regulatory T cells.
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Control of TH17 Cells Occurs in the Small Intestine
Nature.
Jul, 2011 |
Pubmed ID: 21765430 Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified CD4(+) T cell subset distinct from T helper type 1 (T(H)1) and T helper type 2 (T(H)2) cells. T(H)17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of T(H)17 cells have been well characterized. However, where and how the immune system controls T(H)17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory T(H)17 cells can be redirected to and controlled in the small intestine. T(H)17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that T(H)17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory T(H)17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rT(H)17). These results identify mechanisms limiting T(H)17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of T(H)17 cells.
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