Chronic allograft rejection is an immune-promoted pathologic remodeling of allograft tissues which is severe enough to compromise physiologic function. An understanding of this remodeling process requires an understanding of agents that connect alloimmunity with histogenesis. One important connecting agent if TGFbeta which alters leukocyte behavior and stimulates fibrotic tissue remodeling. We believe that chronic TGFbeta production represents a basic pathologic stimulus for the many different histologic features of chronic rejection that appear in different tissues. We have assembled a team of PIs with diverse scientific expertise to study the alloimmune processes that generate TGFbeta, and the mechanisms by which TGFbeta promotes pathogenesis in allografts. Project 1 will use intact animal models to test the hypothesis that alloantibodies stimulate fibrotic remodeling events through macrophages, causing them to produce TGFbeta through chronic Fcgamma and apoptosis receptor engagement. Project 2 will use in vitro studies with human macrophages to investigate the intercellular signaling systems employed when alloantibodies stimulate macrophages via FcgammaR, allowing them to avoid apoptosis and to produce pro- inflammatory cytokines, including TGFbeta. Project 3 will study human and murine allografts to test the hypothesis that transcription reprogramming of stromal cells by the TGFbeta-inducible gene regulator MSY1 drives many of the pathologic developments observed during chronic allograft rejection. Thus, the PIs will attach this problem at the systemic, cellular and genetic levels. They will also provide each other with unique insights and valuable research tools. These projects will be assisted by two core facilities: an Administrative/Statistical Core (Core A) and a Histopathology/Morphometrics Core (Core B). Core A will provider organizational support, secretarial services, budget accounting, and statistical services. Core B will provide the expertise of a veteran transplant pathologist, as well as the technical capabilities for tissue sectioning, histologic and immunohistologic tissue staining, and microscopic and morphometric analyses of stained tissues. In general, this Program Project reflects the efforts of an enthusiastic and highly interactive team of investigators. They have taken advantage of their diverse scientific interests to develop several unique hypotheses and compelling preliminary data regarding the basic biology of chronic allograft rejection. They are well organized, and have strong, active support from their institution.
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