The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Kathryn J. Wood - One of the best experts on this subject based on the ideXlab platform.
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Immunologic unresponsiveness to Alloantigen in vivo: a role for regulatory T cells
Immunological Reviews, 2011Co-Authors: Kathryn J. Wood, Andrew Bushell, Nick D. JonesAbstract:Summary: 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.
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ifn gamma triggered stat1 pkb akt signalling pathway influences the function of Alloantigen reactive regulatory t cells
American Journal of Transplantation, 2010Co-Authors: S Baker, J Wieckiewicz, Kathryn J. WoodAbstract:CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a key role in the induction and maintenance of peripheral tolerance. Rapid and transient production of IFN-γ by Tregs from mice tolerized to Alloantigen in vivo has been shown to be critical for their regulatory function. This IFN-γ has the potential to affect the function of cells present in the same local microenvironment as the Tregs, including the Tregs themselves. Here we investigated the mechanism by which IFN-γ produced by Tregs triggered signaling pathways in Alloantigen reactive Tregs themselves thereby influencing their function in vivo. We show that IFN-γ production and STAT1 activation was increased, while STAT1-dependent PKB/AKT activation was downregulated in Alloantigen reactive Tregs. Further, the activation of STAT1 was blocked in IFN-γ receptor deficient as well as IFN-γ–deficient Tregs, suggesting that IFN-γ produced by the Alloantigen reactive Tregs might act in an autocrine manner to induce STAT1 activation. Importantly, STAT1-deficient Tregs failed to control allograft rejection in vivo. Overall, these findings suggest that the IFN-γ–induced STAT1-PKB/AKT signaling pathway plays a key role in upregulating the ability of Alloantigen reactive Tregs to control graft rejection in vivo.
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ifn γ production by Alloantigen reactive regulatory t cells is important for their regulatory function in vivo
Journal of Experimental Medicine, 2005Co-Authors: Birgit Sawitzki, Cherry I Kingsley, Vanessa Oliveira, Mahzuz Karim, Manuela Herber, Kathryn J. WoodAbstract: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 CD45RBhighCD4+ 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-γ mRNA expression within 24 h of reencountering Alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-γ at the time of cotransfer of Alloantigen reactive T reg cells, together with CD45RBhighCD4+ 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-γ–deficient mice. These data support a unique role for IFN-γ in the functional activity of Alloantigen-reactive T reg cells during the development of operational tolerance to donor Alloantigens in vivo.
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Alloantigen induced cd25 cd4 regulatory t cells can develop in vivo from cd25 cd4 precursors in a thymus independent process
Journal of Immunology, 2004Co-Authors: Mahzuz Karim, Birgit Sawitzki, Andrew Bushell, Cherry I Kingsley, Kathryn J. WoodAbstract: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.
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Regulatory T cells in transplantation tolerance
Nature Reviews Immunology, 2003Co-Authors: Kathryn J. Wood, Shimon SakaguchiAbstract: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.Key PointsRegulation by CD4^+CD25^+ T cells is one of the mechanisms used in vivo to both induce and maintain transplantation tolerance. Alloantigen-specific regulatory T (T_Reg) cells can be generated either in vivo or ex vivo . T_Reg cells are found in the graft, as well as in the peripheral lymphoid tissues, after transplantation. Alloantigen-specific and naturally occurring CD4^+CD25^+ T_Reg cells use similar mechanisms to control immune responsiveness in vivo . Alloantigen-specific T_Reg cells can be augmented by exposure to Alloantigen. CD4^+CD25^+ T_Reg cells are one form of immunoregulation used to control responsiveness to Alloantigens; the relationships between CD4^+CD25^+ T_Reg cells and other populations of regulatory cells remain to be clarified.
Lee M Nadler - One of the best experts on this subject based on the ideXlab platform.
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alloanergization of human t cells results in expansion of Alloantigen specific cd8 cd28 suppressor cells
American Journal of Transplantation, 2014Co-Authors: Christine M Barbon, Jeff K Davies, Annie Voskertchian, R H Kelner, Lisa L Brennan, Lee M Nadler, Eva C GuinanAbstract:Allostimulation with concurrent costimulatory blockade induces Alloantigen-specific hyporesponsiveness in responder T cells (“alloanergization”). Alloanergized responder cells also acquire Alloantigen-specific suppressive activity, suggesting this strategy induces active immune tolerance. While this acquired suppressive activity is mediated primarily by CD4+FOXP3+ cells, other cells, most notably CD8+ suppressor cells, have also been shown to ameliorate human alloresponses. To determine whether alloanergization expands CD8+ cells with allosuppressive phenotype and function, we used mixed lymphocyte cultures in which costimulatory blockade was provided by belatacept, an FDA-approved, second-generation CTLA-4-immunoglobulin fusion protein that blocks CD28-mediated costimulation, as an in vitro model of HLA-mismatched transplantation. This strategy resulted in an eightfold expansion of CD8+CD28− T cells which potently and specifically suppressed alloresponses of both CD4+ and CD8+ T cells without reducing the frequency of a range of functional pathogen-specific T cells. This CD8-mediated allosuppression primarily required cell–cell contact. In addition, we observed expansion of CD8+CD28− T cells in vivo in patients undergoing alloanergized HLA-mismatched bone marrow transplantation. Use of costimulatory blockade-mediated alloanergization to expand allospecific CD8+CD28− suppressor cells merits exploration as an approach to inducing or supporting immune tolerance to Alloantigens after allogeneic transplantation.
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cd2 is involved in maintenance and reversal of human Alloantigen specific clonal anergy
Journal of Experimental Medicine, 1994Co-Authors: Vassiliki A Boussiotis, Gordon J Freeman, James D Griffin, Gary S Gray, John G Gribben, Lee M NadlerAbstract:Induction and maintenance of a state of T cell unresponsiveness to specific Alloantigen would have significant implications for human organ transplantation. Using human histocompatibility leukocyte antigen DR7-specific helper T cell clones, we demonstrate that blockade of the B7 family of costimulatory molecules is sufficient to induce Alloantigen-specific T cell clonal anergy. Anergized cells do not respond to Alloantigen and a variety of costimulatory molecules, including B7-1, B7-2, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule (LFA)-3. However, after culture in exogenous interleukin (IL)-2 for at least 7 d, anergized cells can respond to Alloantigen in the presence of LFA-3. LFA-3 costimulation subsequently restores responsiveness to Alloantigen in the presence of previously insufficient costimulatory signals. Expression of CD2R epitope is downregulated on anergic cells and is restored after 7 d of IL-2 culture. The loss of the CD2R is temporally associated with the inability of anergized cells to respond to LFA-3. These results suggest that in addition to blockade of B7 family members, inhibition of CD2 and, potentially, other costimulatory pathways that might reverse anergy will be necessary to maintain prolonged Alloantigen-specific tolerance.
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b7 but not intercellular adhesion molecule 1 costimulation prevents the induction of human Alloantigen specific tolerance
Journal of Experimental Medicine, 1993Co-Authors: Vassiliki A Boussiotis, Gordon J Freeman, Gary S Gray, John G Gribben, Lee M NadlerAbstract:Presentation of antigen by the major histocompatibility complex to T lymphocytes without the requisite costimulatory signals does not induce an immune response but rather results in a state of antigen-specific unresponsiveness, termed anergy. To determine which costimulatory signals are critical for the T cell commitment to activation or anergy, we developed an in vitro model system that isolated the contributions of Alloantigen and each candidate costimulatory molecule. Here, we show that transfectants expressing HLA-DR7 and either B7 or intercellular adhesion molecule 1 (ICAM-1) deliver independent costimulatory signals resulting in Alloantigen-induced proliferation of CD4-positive T lymphocytes. Although equivalent in their ability to costimulate maximal proliferation of alloreactive T cells, B7 but not ICAM-1 induced detectable interleukin 2 secretion and prevented the induction of Alloantigen-specific anergy. These results are consistent with the hypothesis that blockade of the ICAM-1:lymphocyte function-associated 1 pathway results in immunosuppression, whereas blockade of the B7:CD28/CTLA4 pathway results in Alloantigen-specific anergy. This approach, using this model system, should facilitate the identification of critical costimulatory pathways which must be inhibited in order to induce Alloantigen-specific tolerance before human organ transplantation.
Wenwei Tu - One of the best experts on this subject based on the ideXlab platform.
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efficient induction and expansion of human Alloantigen specific cd8 regulatory t cells from naive precursors by cd40 activated b cells
Journal of Immunology, 2009Co-Authors: Jian Zheng, Pinglung Chan, David A Lewis, Wenwei TuAbstract:Although recent studies have focused on CD4 + regulatory T cells (Treg), CD8 + Treg have also been reported to play important roles in the induction and maintenance of immune tolerance. Adoptive transfer of CD8 + Treg in rodents or induction of CD8 + Treg in humans can prevent or treat allograft rejection and autoimmune diseases. However, no approaches have been reported for the generation of human Ag-specific CD8 + Treg at a practical scale for clinical use. Here, we found that two novel CD8 + T cell subsets with different levels of CD8 surface expression, CD8 high and CD8 low , could be induced from naive CD8 + precursors in vitro by allogeneic CD40-activated B cells, whereas only CD8 high T cells were Alloantigen-specific Treg with relatively poor Alloantigen-specific cytotoxicity. Importantly, Alloantigen-specific CD8 high Treg could be induced and expanded from naive CD8 + CD25 − T cells at a large scale after 3 wk of culture without exogenous cytokines. These induced Alloantigen-specific Treg were CD45RO + and CCR7 − memory cells, and they expressed Foxp3, CD25, CD27, CD28, and CD62L. The induction and expansion of CD8 high Treg by CD40-activated B cells were dependent on endogenously expressed IFN-γ, IL-2, IL-4, and CTLA-4. This approach may facilitate the clinical application of CD8 + Treg-based immunotherapy in transplantation and autoimmune diseases.
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efficient generation of human Alloantigen specific cd4 regulatory t cells from naive precursors by cd40 activated b cells
Blood, 2008Co-Authors: Wenwei Tu, Jian Zheng, Pinglung Chan, Kira Y Dionis, Pascal Schneider, David A LewisAbstract:CD4+CD25+Foxp3+ regulatory T cells (Treg) play an important role in the induction and maintenance of immune tolerance. Although adoptive transfer of bulk populations of Treg can prevent or treat T cell–mediated inflammatory diseases and transplant allograft rejection in animal models, optimal Treg immunotherapy in humans would ideally use antigen-specific rather than polyclonal Treg for greater specificity of regulation and avoidance of general suppression. However, no robust approaches have been reported for the generation of human antigen-specific Treg at a practical scale for clinical use. Here, we report a simple and cost-effective novel method to rapidly induce and expand large numbers of functional human Alloantigen-specific Treg from antigenically naive precursors in vitro using allogeneic nontransformed B cells as stimulators. By this approach naive CD4+CD25− T cells could be expanded 8-fold into Alloantigen-specific Treg after 3 weeks of culture without any exogenous cytokines. The induced Alloantigen-specific Treg were CD45RO+CCR7− memory cells, and had a CD4high, CD25+, Foxp3+, and CD62L (L-selectin)+ phenotype. Although these CD4highCD25+Foxp3+ Alloantigen-specific Treg had no cytotoxic capacity, their suppressive function was cell-cell contact dependent and partially relied on cytotoxic T lymphocyte antigen-4 expression. This approach may accelerate the clinical application of Treg-based immunotherapy in transplantation and autoimmune diseases.
David A Lewis - One of the best experts on this subject based on the ideXlab platform.
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efficient induction and expansion of human Alloantigen specific cd8 regulatory t cells from naive precursors by cd40 activated b cells
Journal of Immunology, 2009Co-Authors: Jian Zheng, Pinglung Chan, David A Lewis, Wenwei TuAbstract:Although recent studies have focused on CD4 + regulatory T cells (Treg), CD8 + Treg have also been reported to play important roles in the induction and maintenance of immune tolerance. Adoptive transfer of CD8 + Treg in rodents or induction of CD8 + Treg in humans can prevent or treat allograft rejection and autoimmune diseases. However, no approaches have been reported for the generation of human Ag-specific CD8 + Treg at a practical scale for clinical use. Here, we found that two novel CD8 + T cell subsets with different levels of CD8 surface expression, CD8 high and CD8 low , could be induced from naive CD8 + precursors in vitro by allogeneic CD40-activated B cells, whereas only CD8 high T cells were Alloantigen-specific Treg with relatively poor Alloantigen-specific cytotoxicity. Importantly, Alloantigen-specific CD8 high Treg could be induced and expanded from naive CD8 + CD25 − T cells at a large scale after 3 wk of culture without exogenous cytokines. These induced Alloantigen-specific Treg were CD45RO + and CCR7 − memory cells, and they expressed Foxp3, CD25, CD27, CD28, and CD62L. The induction and expansion of CD8 high Treg by CD40-activated B cells were dependent on endogenously expressed IFN-γ, IL-2, IL-4, and CTLA-4. This approach may facilitate the clinical application of CD8 + Treg-based immunotherapy in transplantation and autoimmune diseases.
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efficient generation of human Alloantigen specific cd4 regulatory t cells from naive precursors by cd40 activated b cells
Blood, 2008Co-Authors: Wenwei Tu, Jian Zheng, Pinglung Chan, Kira Y Dionis, Pascal Schneider, David A LewisAbstract:CD4+CD25+Foxp3+ regulatory T cells (Treg) play an important role in the induction and maintenance of immune tolerance. Although adoptive transfer of bulk populations of Treg can prevent or treat T cell–mediated inflammatory diseases and transplant allograft rejection in animal models, optimal Treg immunotherapy in humans would ideally use antigen-specific rather than polyclonal Treg for greater specificity of regulation and avoidance of general suppression. However, no robust approaches have been reported for the generation of human antigen-specific Treg at a practical scale for clinical use. Here, we report a simple and cost-effective novel method to rapidly induce and expand large numbers of functional human Alloantigen-specific Treg from antigenically naive precursors in vitro using allogeneic nontransformed B cells as stimulators. By this approach naive CD4+CD25− T cells could be expanded 8-fold into Alloantigen-specific Treg after 3 weeks of culture without any exogenous cytokines. The induced Alloantigen-specific Treg were CD45RO+CCR7− memory cells, and had a CD4high, CD25+, Foxp3+, and CD62L (L-selectin)+ phenotype. Although these CD4highCD25+Foxp3+ Alloantigen-specific Treg had no cytotoxic capacity, their suppressive function was cell-cell contact dependent and partially relied on cytotoxic T lymphocyte antigen-4 expression. This approach may accelerate the clinical application of Treg-based immunotherapy in transplantation and autoimmune diseases.
Bruce R Blazar - One of the best experts on this subject based on the ideXlab platform.
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elevation of intracellular cyclic amp in alloreactive cd4 t cells induces Alloantigen specific tolerance that can prevent gvhd lethality in vivo
Biology of Blood and Marrow Transplantation, 2007Co-Authors: Matthew J Oshaughnessy, Patricia A Taylor, Vassiliki A Boussiotis, Angela Panoskaltsismortari, Zong Ming Chen, Irene Gramaglia, Christine Vogtenhuber, Ed Palmer, Thomas Graderbeck, Bruce R BlazarAbstract:Abstract Cyclic AMP (cAMP) is an important negative regulator of T cell activation, and an increased level of cAMP is associated with T cell hyporesponsiveness in vitro. We sought to determine whether elevating intracellular cAMP levels ex vivo in alloreactive T cells during primary mixed lymphocyte reactions (MLR) is sufficient to induce Alloantigen-specific tolerance and prevent graft-versus-host disease (GVHD). Primary MLRs were treated with exogenous 8 Br-cAMP and IBMX, a compound that increases intracellular cAMP levels by inhibition of phosphodiesterases. T cell proliferation and IL-2 responsiveness in the treated primary MLR cultures were greatly reduced, and viable T cells recovered on day 8 also had impaired responses to restimulation with Alloantigen compared to control-treated cells, but without an impairment to nonspecific mitogens. Labeling experiments showed that cAMP/IBMX inhibited alloreactive T cell proliferation by limiting the number of cell divisions, increasing susceptibility to apoptosis, and rendering nondeleted alloreactive T cells hyporesponsive to Alloantigen restimulation. cAMP/IBMX-treated CD4 + T cells had a markedly reduced capacity for GVHD lethality in major histocompatibility complex class II disparate recipients, but maintained the capacity to mediate other CD4 + T cell responses in vivo. Thus, our results provide the first preclinical evidence of using cAMP-elevating pharmaceutical reagents to achieve long-term Alloantigen-specific T cell tolerance that is sufficient to prevent GVHD.
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cd4 cd25 immune regulatory cells are required for induction of tolerance to Alloantigen via costimulatory blockade
Journal of Experimental Medicine, 2001Co-Authors: Patricia A Taylor, Randolph J Noelle, Bruce R BlazarAbstract:Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4+CD25+ cells regulate T cell responses to Alloantigen and are critical for tolerance induction, murine CD4+ T cells were tolerized to Alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte–associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to Alloantigen in vivo. CD4+CD25+ T cells were found to be potent regulators of alloresponses. Depletion of CD4+CD25+ T cells from the CD4+ responder population completely abrogated ex vivo tolerance induction to Alloantigen as measured by intact responses to Alloantigen restimulation in vitro and in vivo. Addback of CD4+CD25+ T cells to CD4+CD25− cultures restored tolerance induction. These data are the first to indicate that CD4+CD25+ cells are essential for the induction of tolerance to Alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.
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induction of cd4 t cell Alloantigen specific hyporesponsiveness by il 10 and tgf β
Journal of Immunology, 1999Co-Authors: Jay C Zeller, Angela Panoskaltsismortari, William J Murphy, Francis W Ruscetti, Satwant K Narula, M G Roncarolo, Bruce R BlazarAbstract:Induction and maintenance of Ag-specific tolerance are pivotal for immune homeostasis, prevention of autoimmune disorders, and the goal of transplantation. Recent studies suggest that certain cytokines, notably IL-10 and TGF-β, may play a role in down-regulating immune functions. To further examine the role of cytokines in Ag-specific hyporesponsiveness, murine CD4 + T cells were exposed ex vivo to Alloantigen-bearing stimulators in the presence of exogenous IL-10 and/or TGF-β. Primary but not secondary Alloantigen proliferative responses were inhibited by IL-10 alone. However, the combined addition of IL-10 + TGF-β markedly induced Alloantigen hyporesponsiveness in both primary and secondary MLR cultures. Alloantigen-specific hyporesponsiveness was observed also under conditions in which nominal Ag responses were intact. In adoptive transfer experiments, IL-10 + TGF-β-treated CD4 + T cells, but not T cells treated with either cytokine alone, were markedly impaired in inducing graft-vs-host disease alloresponses to MHC class II disparate recipients. These data provide the first formal evidence that IL-10 and TGF-β have at least an additive effect in inducing Alloantigen-specific tolerance, and that in vitro cytokines can be exploited to suppress CD4 + T cell-mediated Ag-specific responses in vivo.