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Tolerogenic Dendritic Cells (tolerogenic + dendritic_cell)
Selected AbstractsTolerogenic Dendritic Cells: All Present and Correct?AMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. W. Thomson Although well-recognized for their sentinel role and, when activated, their immunostimulatory function, bone marrow-derived dendritic cells (DC) possess inherent tolerogenic (tol) ability. Under quiescent conditions, these cells maintain central and peripheral self tolerance. When appropriately conditioned, in vitro or in vivo, they inhibit innate and adaptive immunity to foreign antigens, including memory T-cell responses. This suppressive function is mediated by various mechanisms, including the expansion and induction of antigen-specific regulatory T cells. Extensive experience in rodent models and recent work in nonhuman primates, indicate the potential of pharmacologically-modified, tol DC (tolDC) to regulate alloimmunity in vivo and to promote lasting, alloantigen-specific T-cell unresponsiveness and transplant survival. While there are many questions yet to be addressed concerning the functional biology of tolDC in humans, these cells offer considerable potential as natural, safe and antigen-specific regulators for long-term control of the outcome of organ and hematopoietic cell transplantation. This minireview surveys recent findings that enhance understanding of the functional biology and therapeutic application of tolDC, with special reference to transplantation. [source] Tolerogenic dendritic cells pulsed with enterobacterial extract suppress development of colitis in the severe combined immunodeficiency transfer modelIMMUNOLOGY, Issue 4 2007A. E. Pedersen Summary Immunomodulatory dendritic cells (DCs) that induce antigen-specific T-cell tolerance upon in vivo adoptive transfer are promising candidates for immunotherapy of autoimmune diseases. The feasibility of such a strategy has recently proved its efficacy in animal models of allotransplantation and experimental allergic encephalitis, but the effect in inflammatory bowel disease has not yet been demonstrated. In severe combined immunodeficient (SCID) mice, adoptively transferred CD4+ CD25, T cells repopulate the lymphoid tissues and lead to development of chronic colitis characterized by CD4+ T-cell proliferation against enterobacterial extract in vitro. In this model, we adoptively transferred in-vitro -generated bone-marrow-derived DCs exposed to interleukin-10 (IL-10) and an enterobacterial extract. We show that these cells are CD11c positive with intermediate expression of CD40, CD80 and CD86 and have a diminished secretion of IL-6, IL-12 p40/70, tumour necrosis factor-, and keratinocyte-derived chemokine (KC) compared to DCs treated with enterobacterial extract alone. In vivo, these cells prevented weight loss in SCID mice adoptively transferred with CD4+ CD25, T cells, resulted in a lower histopathology colitis score and tended to result in higher serum levels of IL-1,, IL-10, IL-12, IL-13, IL-17, KC and monokine induced by interferon-gamma (MIG). These data underscore the potential of using immunomodulatory DCs to control inflammatory bowel disease and demonstrate its potential use in future human therapeutic settings. [source] Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Yingzi Cong Abstract The gut is home to a large number of Treg, with both CD4+ CD25+ Treg and bacterial antigen-specific Tr1 cells present in normal mouse intestinal lamina propria. It has been shown recently that intestinal mucosal DC are able to induce Foxp3+ Treg through production of TGF-, plus retinoic acid (RA). However, the factors instructing DC toward this mucosal phenotype are currently unknown. Curcumin has been shown to possess a number of biologic activities including the inhibition of NF-,B signaling. We asked whether curcumin could modulate DC to be tolerogenic whose function could mimic mucosal DC. We report here that curcumin modulated BM-derived DC to express ALDH1a and IL-10. These curcumin-treated DC induced differentiation of naïve CD4+ T cells into Treg resembling Treg in the intestine, including both CD4+CD25+ Foxp3+ Treg and IL-10-producing Tr1 cells. Such Treg induction required IL-10, TGF-, and retinoic acid produced by curcumin-modulated DC. Cell contact as well as IL-10 and TGF-, production were involved in the function of such induced Treg. More importantly, these Treg inhibited antigen-specific T-cell activation in vitro and inhibited colitis due to antigen-specific pathogenic T cells in vivo. [source] Regulatory T Cells Are Critical to Tolerance Induction in Presensitized Mouse Transplant Recipients Through Targeting Memory T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010W. Ge Memory T cells are a significant barrier to induction of transplant tolerance. However, reliable means to target alloreactive memory T cells have remained elusive. In this study, presensitization of BALB/c mice with C57BL/6 skin grafts generated a large number of OX40+CD44hieffector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti-OX40L monoclonal antibody (mAb) (,-OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, ,-OX40L was added to the combined treatment protocol of LF15,0195 (LF) and anti-CD45RB (,-CD45RB) mAb,a protocol that induced heart allograft tolerance in non-presensitized recipients but failed to induce tolerance in presensitized recipients. Interestingly, this triple therapy restored donor-specific heart allograft tolerance in our presensitized model that was associated with induction of tolerogenic dendritic cells and CD4+CD25+Foxp3+ T regulatory cells (Tregs). Of note, CD25+ T cell depletion in triple therapy recipients prevented establishment of allograft tolerance. In addition, adoptive transfer of donor-primed effector/memory T cells into tolerant recipients markedly reduced levels of Tregs and broke tolerance. Our findings indicated that targeting memory T cells, by blocking OX40 costimulation in presensitized recipients was very important to expansion of Tregs, which proved critical to development of tolerance. [source] Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft ToleranceAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009W. Ge The inherent immunosuppressive properties and low immunogenicity of mesenchymal stems cells (MSCs) suggested their therapeutic potential in transplantation. We investigated whether MSCs could prolong allograft survival. Treatment involving infusion of MSCs into BALB/c recipients 24 hours after receiving a heart allograft from a C57BL/6 donor significantly abated rejection and doubled graft mean survival time compared to untreated recipients. Furthermore, combination therapy of MSCs and low-dose Rapamycin (Rapa) achieved long-term heart graft survival (>100 days) with normal histology. The treated recipients readily accepted donor skin grafts but rejected third-party skin grafts, indicating the establishment of tolerance. Tolerant recipients exhibited neither intragraft nor circulating antidonor antibodies, but demonstrated significantly high frequencies of both tolerogenic dendritic cells (Tol-DCs) and CD4+CD25+Foxp3+T cells in the spleens. Infusion of GFP+C57BL/6-MSCs in combination with Rapa revealed that the GFP-MSCs accumulated in the lymphoid organs and grafts of tolerant recipients. Thus, engraftment of infused MSCs within the recipient's lymphoid organs and allograft appeared to be instrumental in the induction of allograft-specific tolerance when administered in combination with a subtherapeutic dose of Rapamycin. This study supports the clinical applicability of MSCs in transplantation. [source] | ||||||||||