Functional Activity of Natural Antibody is Altered in Cr2-deficient Mice

Journal of Immunology (Baltimore, Md. : 1950). Nov, 2002  |  Pubmed ID: 12421918

The major source of natural IgM Abs are B-1 cells, which differ from conventional B cells in their anatomic location, cell surface phenotype, restricted usage of particular V(H) genes and limited use of N-region addition during V-D-J rearrangement. The origin of B-1 cells is unclear. However, they are capable of self-renewal and their development is sensitive to signaling via the B cell receptor, as genetic defects that impair the strength of the signal often result in limited development. These findings suggest that B-1 cells require either an intrinsic signal, or contact with Ag, for positive selection and expansion and/or maintenance in the periphery. In support of interaction with cognate Ag, deficiency in the complement receptors CD21/CD35 results in a 30-40% decrease in the CD5(+) B-1 population. To determine whether this reduction reflects a loss of certain specificities or simply a proportional decline in the repertoire, we examined peritoneal B cells isolated from Cr2(+) and Cr2(def) mice for recognition of a B-1 cell Ag, i.e., phosphatidylcholine, and assayed for injury in an IgM natural Ab-dependent model of reperfusion injury. We found a similar frequency of phosphatidylcholine-specific CD5(+) B-1 cells in the two strains of mice. By contrast, the Cr2(def) mice have reduced injury in the IgM-dependent model of reperfusion injury. Reconstitution of the deficient mice with pooled IgM or adoptive transfer of Cr2(+) peritoneal B cells restored injury. These results suggest that complement receptors CD21/CD35 are important in maintenance of the B-1 cell repertoire to some, but not all, specificities.

Lymphocyte-rich Classical Hodgkin's Lymphoma: Clinical Presentation and Treatment Outcome in 100 Patients Treated Within German Hodgkin's Study Group Trials

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Aug, 2005  |  Pubmed ID: 16009944

To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL).

CD40-activated B Cells Express Full Lymph Node Homing Triad and Induce T-cell Chemotaxis: Potential As Cellular Adjuvants

Blood. Apr, 2006  |  Pubmed ID: 16357329

CD40-activated B cells (CD40-B cells) have previously been introduced as an alternative source of antigen-presenting cells for immunotherapy. CD40-B cells can prime naive and expand memory T cells, and they can be generated in large numbers from very small amounts of peripheral blood derived from healthy individuals or cancer patients alike. Administration of CD40-B cells as a cellular adjuvant would require these cells to migrate toward secondary lymphoid organs and attract T cells in situ, processes guided by specific chemokines and chemokine receptors. Here, we demonstrate that primary, human CD40-B cells express a pattern of adhesion molecules and chemokine receptors necessary for homing to secondary lymphoid organs and have the capacity to migrate to cognate ligands. Furthermore, we show that CD40-B cells express important T-cell attractants and induce strong T-cell chemotaxis. These findings further support the use of CD40-B cells as cellular adjuvant for cancer immunotherapy.

Statins Inhibit Human APC Function: Implications for the Treatment of GVHD

Blood. Aug, 2008  |  Pubmed ID: 18684883

The Use of Statins in Hematopoietic Stem Cell Transplantation

Current Stem Cell Research & Therapy. Dec, 2009  |  Pubmed ID: 19500062

Hematopoietic stem cell transplantation has become an established treatment for some patients with malignant and non-malignant hematologic diseases. More wide-spread use of this treatment modality is limited by its severe side effects. Graft-versus-host disease is a major cause of morbidity and mortality following allogeneic stem transplantation. Recent data from experimental research in murine models of GVHD and early stage clinical studies demonstrate the potential of statins in the prevention and treatment of acute and chronic GVHD. Statins are lipid lowering drugs, which reduce cholesterol production by inhibiting HMG-CoA reductase, the rate limiting enzyme of the mevalonate pathway. They are an already approved drug class with a well known toxicity profile. Besides lowering of cholesterol levels other pleiotropic effects contribute to the therapeutic activity of statins. Statins have immunomodulatory effects and inhibit a broad range of immune cells that play a role in the pathogenesis of GVHD, including antigen-presenting cells. In addition to preventing GVHD statins possess several other effects that might prove beneficial in the setting of allogeneic transplantation, such as cardiovascular protection and anti-neoplastic activity. Here we review the current knowledge on the use and effects of statins in patients who undergo allogeneic hematopoietic stem cell transplantation with a special focus on prevention and treatment of GVHD.

Activated Human B Cells: Stimulatory or Tolerogenic Antigen-presenting Cells?

Blood. Jul, 2009  |  Pubmed ID: 19608762

The Shared Tumor Associated Antigen Cyclin-A2 is Recognized by High-avidity T-cells

International Journal of Cancer. Journal International Du Cancer. Nov, 2009  |  Pubmed ID: 19681121

Cyclin-A2, a key cell cycle regulator, has been shown to be overexpressed in various types of malignancies with little expression in normal tissue. Such tumor-associated genes potentially are useful targets for cancer immunotherapy. However, high-avidity cyclin-specific T cells are considered to be thymically deleted. We identified at least one nonameric HLA-A*0201 binding cyclin-A2 epitope by a reverse immunology approach. Using a highly efficient T-cell expansion system that is based on CD40-activated B (CD40-B) cells as sole antigen-presenting cells we successfully generated cyclin-A2 specific CTL from HLA-A*0201(+) donors. Interestingly, high-avidity cyclin-A2 specific CTL lines, which recognized peptide-pulsed and antigen expressing target cells, were indeed generated by stimulation with CD40-B cells when pulsed with low concentrations of peptide, whereas CD40-B cells pulsed at saturating concentrations could only induce low-avidity CTL, which recognized peptide-pulsed target cells only. One high-avidity CTL line was subcloned and CTL clones, whose peptide concentration required for half-maximal lysis were less than 1 nM, could lyse cyclin-A2 expressing tumor cells. Taken together, cyclin A2 is an attractive candidate for immune intervention in a significant number of cancer patients and high-avidity T cells can be readily generated using CD40-B cells as antigen-presenting cells.

The Role of B Cells in the Pathogenesis of Graft-versus-host Disease

Blood. Dec, 2009  |  Pubmed ID: 19749094

Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.

T-cell Responses to Cyclin B1 Are Not Restricted to P53-overexpressing Tumors

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Nov, 2009  |  Pubmed ID: 19903794

Acquired Long QT Syndrome and Torsade De Pointes Associated with HIV Infection

Case Reports in Medicine. 2010  |  Pubmed ID: 20827440

Here, we report the case of an HIV infected patient that was treated for pneumonia with a macrolid antibiotic. The patient experienced a prolongation of the already pathologic QTc interval resulting in repeated torsades de pointes necessitating CPR and implantation of an AICD. This case exemplifies that torsades de pointes due to acquired long QT syndrome is a serious and potentially fatal complication in HIV-positive patients.

CCC Meets ICU: Redefining the Role of Critical Care of Cancer Patients

BMC Cancer. 2010  |  Pubmed ID: 21059210

Currently the majority of cancer patients are considered ineligible for intensive care treatment and oncologists are struggling to get their patients admitted to intensive care units. Critical care and oncology are frequently two separate worlds that communicate rarely and thus do not share novel developments in their fields. However, cancer medicine is rapidly improving and cancer is eventually becoming a chronic disease. Oncology is therefore characterized by a growing number of older and medically unfit patients that receive numerous novel drug classes with unexpected side effects.

Improvement of Platelet Dysfunction in Chronic Myelogenous Leukemia Following Treatment with Imatinib: a Case Report

Journal of Medical Case Reports. 2011  |  Pubmed ID: 21624109

In patients with chronic myeloid leukemia, tyrosine kinase inhibitors suppress the BCR-ABL+ clone and often induce complete molecular remissions. Megakaryocytes in such patients have been shown to be derived from the BCR-ABL+ clone, and abnormal platelet function is frequent in chronic myeloid leukemia. However, little is known about the influence of modern targeted therapy on chronic myeloid leukemia-associated platelet disorders.

Activated Primary Human B Cells Efficiently Induce Early CD40L and CD107a Expression in CD4+ T Cells

Blood. Nov, 2011  |  Pubmed ID: 22123910

Analysis of Tie2-Expressing Monocytes (TEM) in Patients With Colorectal Cancer

Cancer Investigation. Dec, 2011  |  Pubmed ID: 22171993

Tie2-expressing monocytes (TEM) promote tumor angiogenesis and growth in experimental cancer models. The role of TEM in cancer patients is unknown. We studied TEM in healthy volunteers and colorectal cancer (CRC) patients. Although TEM were detectable in the blood and tumor lesions of CRC patients, their frequency and functional phenotype showed no correlation with levels of angiopoietin-2 or vascular endothelial growth factor, microvessel density, tumor markers, tumor stage, or outcome of antiangiogenic therapy. These unexpected findings are at odds with murine tumor models and question the diagnostic or therapeutic value of TEM in human cancer.

Intermediate Intensity Conditioning Regimen Containing FLAMSA, Treosulfan, Cyclophosphamide, and ATG for Allogeneic Stem Cell Transplantation in Elderly Patients with Relapsed or High-risk Acute Myeloid Leukemia

Annals of Hematology. Jan, 2012  |  Pubmed ID: 21584670

Lower dosage of total body irradiation (TBI) and chemotherapy in reduced-intensity conditioning (RIC) regimens prior to allogeneic stem cell transplantation have reduced the toxicity of the conditioning and non-relapse mortality. The FLAMSA-RIC protocol for high-risk patients with acute myeloid leukemia (AML) and myelodysplastic syndrome has shown promising results in refractory disease as well as in first complete remission. Still, the RIC protocol containing 4 Gy TBI/cyclophosphamide/anti-thymocyte globulin (ATG) implicates acute toxicity mainly due to TBI preventing its usage in patients with advanced age and/or severe co-morbidities. To increase feasibility and safety of the conditioning, we substituted TBI with treosulfan. Seventeen patients with relapsed or high-risk AML and either advanced age or concomitant disease were treated within a preparative regimen containing a 4-day course of chemotherapy (FLAMSA) followed by RIC comprising of treosulfan, cyclophosphamide, and ATG. After median follow-up of 12 months, the estimated incidences of relapse and non-relapse mortality were 25% and 20%, respectively. One-year overall survival was 62%. In conclusion, FLAMSA-treosulfan/cyclophosphamide/ATG is an intermediate intensity conditioning regimen with acceptable non-relapse mortality for patients with relapsed or high-risk AML. Substituting TBI with treosulfan provides an alternative to treat elderly patients or patients with severe co-morbidities when TBI appears not feasible due to the potential of increased toxicity.