Numerous clinical and animal studies have demonstrated that alloantibodies promote the development of chronic allograft rejection. Despite this, very little is known about the immunobiology and pathobiology of post-transplant donor reactive alloantibodies in transplant recipients. The proposed studies will initially employ ELISA and ELISPOT assays to generate definitive information on the patterns of donor MHC class I- and class II-reactive alloantibodies that are produced post-transplant in murine and human allograft recipients (Specific Aim 1). Since chronic allograft rejection is an immune-induced tissue remodeling disease, it basic pathologic mechanism must involve agents that link alloimmunity with histogenesis. And TGFbeta within allografts. While this relationship involves T and B cells, it appears to focus on macrophages in two ways. One way involves an alloantibody/FCgammaR/TGFbeta axis; the other involves an alloantibody/apoptosis/TGFbeta axis. Both axes result in chronic TGFbeta production, which subsequently modulates T cell behavior, alloantibody production and tissue histogenesis. The studies in Specific Aim 2 employ murine cardiac allografts to test the hypothesis that alloantigen/alloantibody complexes trigger FcgammaR on graft infiltrating macrophages, causing them to chronically produce activate TGFbeta. The studies in Specific Aim 3 test the hypothesis that donor MHC-reactive alloantibodies directly induce the apoptosis of graft cells, which, in turn, triggers apoptosis receptors on graft-infiltrating macrophages, causing them to chronically produce TGFbeta. The latter hypothesis will be tested in vitro and in vivo in both mice and humans. In the course of the proposed studies, we will explore many important conceptual and mechanistic issues regarding the relationship of alloantibodies to chronic allograft rejection.
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