This is Project 3 of the consortium proposal focused on the manipulation of hematopoietic and mesenchymal stem cells for the control of donor-specific alloreactivity in Cynomolgus monkeys. This project will define the role of regulatory T cells and cytokines in allograft acceptance of allogeneic islet and kidney transplantation. A central role of T immune regulatory cells in the maintenance of transplant tolerance is an emerging concept requiring critical evaluation in non-human primate models of allograft transplantation. Early studies with murine transplantation models had suggested that suppression of Thl cytokine responses, primarily IFN-gamma, and enhancement of Th2 responses, primarily IL-4, were critical for tolerance. These observations were consistent with the prevailing concepts that IL-4 could negatively regulate Thl cytokine responses and that IFN-gamma was proinflammatory. More recently the cytokines IL-l0 and TGF-beta, which have anti-inflammatory properties, have been implicated in the maintenance of tolerance. Specifically, a subset of CD4+ T cells, designated T regulatory cells, has been demonstrated to inhibit antigen-specific immune responses through the secretion of IL-l0 and TGF-beta and expression of CTLA-4. T regulatory cells have been identified in models of autoimmunity and allograft tolerance in mice and humans. This has led to a compelling new hypothesis of allograft tolerance in which T regulatory cells, producing IL-l0 and/or TGFbeta, are the primary mediators of peripheral allograft tolerance. Under this hypothesis, the tolerant state is a dynamic one in which proinflammatory cells are held in check by T regulatory cells. Our murine model of tolerance involving co transplantation of intact active bone fragments (JAB) and transient costimulation blockade results in stable, long-term tolerance. Investigations into the mechanism maintaining the tolerant state suggest a role for IL-l0-producing T regulatory cells. Preliminary results in a Cynomolgus monkey that accepted an allogeneic kidney graft for more than 145 days are also consistent with a hypothesis that, in immunologically intact recipients, a dominance of T regulatory cells over proinflammatory T cells produces long-term allograft acceptance. Here we propose to test whether allograft tolerance induced by non-myeloablative regimens in the setting of allogeneic islet and renal transplantation in non-human primates depends on a dominant T regulatory cell population. We also propose to test whether bone marrow- derived mesenchymal stem cells can enhance the development of T regulatory cells. We anticipate that these mechanistic studies will lead to an increased understanding of the roles of cytokines and T regulatory cells in allograft acceptance and tolerance. Our proposed studies will also evaluate ex vivo cytokine assays as biomarkers of immune tolerance.
Showing the most recent 10 out of 11 publications
