Developing approaches to induce and maintain robust cardiac allograft is the ideal solution to the morbidity and mortality associated with chronic immunosuppression. We uniquely demonstrated that kidney transplant tolerance in mice, swine and NHP remarkably facilitates heart transplant tolerance. Understanding the mechanisms underlying these observations has broad implications for the transplant community well beyond the relatively small numbers of patients likely to receive kidney/heart cotransplants. The deciphered mechanisms could guide novel therapeutic approaches to induce tolerance to heart grafts (among other tolerance-resistant organs) in the absence of a kidney, or improve outcomes without inducing tolerance. Elucidating mechanisms of kidney induced cardiac allograft tolerance (KICAT) is the focus of this Program. Our preliminary results in murine, swine, and NHP models implicate regulatory T cells (Treg) as the end effectors of KICAT with kidney-specific cells (e.g. plasmacytoid dendritic cells (pDC), renal tubular epithelial cells (RTEC)) and/or cell products (i.e. erythropoietin (EPO)) amplifying those regulatory mechanisms. Indeed, new data indicate that erythropoietin (EPO), a hormone produced by the adult kidney and formerly thought only to induce red blood cell development, mediates kidney tolerance by functioning as a Treg-enhancing immunosuppressant. Together our joint data support the hypothesis that: high local concentrations of EPO in the donor kidney graft directly inhibit pathogenic effector T cells and induce TGF? production by RTEC and kidney pDC that facilitate generation and stability of donor-reactive Tregs. These Treg crucially mediate heart graft tolerance. To test this hypothesis we have designed a Program consisting of 3 interactive Projects (2 at MGH, Boston and one at Mount Sinai, NY) that use murine and NHP models. P. Heeger (Mount Sinai, NY, Project 3) will test mechanisms of EPO-induced kidney transplant tolerance in mice. The Project will 1) determine the effects of kidney allograft-derived EPO on murine alloimmunity and allograft survival, 2) decipher the mechanisms through which EPO inhibits conventional alloreactive T cells, and 3) test the mechanisms of EPO on Treg induction and stability. R. Colvin and colleagues (MGH, Project 2) will use murine models of kidney and heart/kidney transplantation to 1) determine the general immunobiologic features of kidney induced systemic tolerance, 2) test whether KICAT is due to regulatory or deletional tolerance, and 3) test the hypothesis that specific kidney derived cells and mediators are responsible for tolerance induction. J. Madsen and colleagues (MGH, Project 1) will 1) characterize the overall robustness of the tolerant state induced by KICAT, 2) determine the role of regulatory T cells in KICAT, and 3) test the hypothesis that renal pDCs and EPO are required for KICAT. An immunopathology core (Core A) and the administrative core will support all 3 Projects. This Program is integrated such that early advances from mouse models will inform and refine the studies in NHP while clinical discoveries in NHP will be assessed mechanistically in the mouse.
Achieving long term survival of organ transplants without the need for chronic immunosuppression will provide transplants recipients with a healthier and longer life. These studies will explore ways to eliminate the need for chronic immunosuppressive drugs in patients undergoing heart transplantation. Project-001: Induction of Tolerance to Heart Allograft in Nonhuman Primates by Donor Kidney Co-Transplantation Project Leader (PL): Joren C. Madsen DESCRIPTION (as provided by applicant): Protocols that achieve tolerance of kidney allografts in nonhuman primates (and in humans) fail to induce tolerance of heart allografts. We have taken advantage of the intrinsic tolerogenicity of kidney allografts and, through donor kidney cotransplantation, have achieved stable tolerance of heart allografts in nonhuman primates (NHP) which, if transplanted alone, are rejected acutely. The consistency with which kidney allografts confer tolerance upon recipients of cotransplanted heart allografts across different species (mouse, swine, NHP), across different histocompatibility barriers, and across different tolerance protocols is compelling. Registry studies furthermore confirm that human recipients of kidney and heart allografts from the same donor experience less acute rejection and less cardiac allograft vasculopathy (CAV) compared to those receiving heart transplants alone. Understanding the mechanisms underlying these unique observations has broad implications for the transplant community, well beyond the relatively small numbers of patients likely to receive kidney/heart cotransplants. Once these mechanisms are better understood, they could be exploited to guide novel therapeutic approaches that induce tolerance to heart allografts (and other tolerance-resistant organs) in the absence of a kidney, or improve outcomes without inducing tolerance. The mechanisms driving kidney- induced cardiac allograft tolerance (KICAT) and its implications for human heart transplant recipients is the focus of this Project. Our preliminary results in murine, swine, and NHP models implicate regulatory T cells (Treg) as the end effectors of KICAT with kidney-specific cells (e.g. plasmacytoid dendritic cells (pDC)) and/or cell products (i.e. erythropoietin (EPO)) amplifying those regulatory mechanisms. Indeed, emerging data from Heeger's group suggest that the unique ability of the kidney to induce tolerance is mediated in part by erythropoietin (EPO), a hormone traditionally thought to only be responsible for erythropoiesis but newly shown to function as a Treg-enhancing immunosuppressant. Together, our joint data support the following working model: high local concentrations of EPO in the donor kidney graft directly inhibit pathogenic effector T cells and promote the ability of kidney pDC to facilitate the generation and stability of donor-reactive Tregs via TGF? production. The enhanced activity of host Tregs induced by donor kidney elements leads to a robust state of heart allograft tolerance. Our goals are to test this model by determining the specific roles of Tregs, pDC, EPO and TGF? in achieving KICAT in NHPs and to characterize the robustness of the tolerance induced by KICAT in anticipation of clinical application. The newly acquired knowledge will be used to develop novel strategies to improve heart transplant outcomes and to induce tolerance of other highly resistant allografts.
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