UNIVERSITY OF CHICAGO, THE
Tolerance to allogeneic grafts can be achieved in a number of rodent models, and long-term graft survival has been reported in a number of non-human primate models. A consistent feature of stable graft acceptance is the control of alloantibody production; conversely, the appearance of increasing alloantibody titers portends graft rejection. Two divergent interpretations have been advanced to explain these observations- first, that the activation of alloreactive B cells and alloantibodies are simply markers of alloreactive T cell activation and that T cells are solely responsible for the loss of the allograft; second, alloreactive B cells and alloantibodies contribute to graft rejection; either directly or indirectly by synergizing with alloreactive T cells or other effector cells. Because of the well-characterized pathogenic properties of B cells and alloantibodies, we favor the second interpretation and hypothesize that the control of alloreactive B cells, in addition to T cells, is central to stable tolerance. Indeed, the unexpected efficacy of B cell-directed immunotherapy in controlling a number of autoimmune diseases and transplant rejection, pathologies initially thought to be predominantly T cell- mediated, suggests an important role for B cells in these clinical settings. The fate of alloreactive T cells has been extensively defined in various models of transplantation tolerance, but there is virtually no information regarding the fate of alloreactive B cells. We have addressed this disparity by developing a novel experimental model to visualize the fate of alloreactive B cells. We observed that transplantation tolerance is associated with the deletion of the mature alloreactive B cells, and a sparing/enrichment of the transitional/immature alloreactive B cells. These observations are consistent with recent reports of a correlation between altered B cell subsets and tolerance in non-human primates and enriched B cell markers in bio-marker studies of spontaneously tolerant kidney transplant recipients. Thus the overall goal of our proposed studies is to define the role of B cells in the induction and maintenance of transplantation tolerance. The first specific aim is to define the mechanistic basis for the selective deletion of mature alloreactive B cells, and to test whether this deletion is essential for the development and/or maintenance of allograft tolerance. The second aim is to further characterize the preserved immature/transitional alloreactive B cells and test whether these cells contribute to the development or maintenance of tolerance. The third specific aim is to determine whether clinically relevant events, that are either T-dependent or T-independent, can reverse B cell tolerance and precipitate graft rejection. We anticipate that these studies will provide insights into the role of B cells in transplantation tolerance, and contribute to the development of a clinical strategy that induces and maintains long-term graft survival in the absence of pharmacologic immunosuppression. PUBLIC HEALTH RELEVANCE: The induction of transplantation tolerance for achieving long-term allograft survival in the absence of non- specific and continuous immunosuppression is an important clinical goal. In contrast to most investigations that focus on alloreactive T cells, the studies in this proposal are aimed at defining the role of B cells in transplantation tolerance, and will test whether an independent control of alloreactive B cells is necessary for stable long-term allograft tolerance. We anticipate that these studies will contribute to the development of a clinical strategy that can induce and maintain stable allograft tolerance.