Allogeneic kidney transplantation is a well-established approach for the therapy of end stage renal disease in humans. The long term survival of renal allografts has been limited, however, by the development of acute and chronic rejection, and remains at only 40-50% at 8-10 years. Much experimental evidence in both animal models and humans implicate alloreactive T lymphocytes as central mediators of the rejection processes. These T cells recognize both allogeneic MHC/peptide complexes expressed directly on the transplanted graft (direct pathway) and processed donor antigens expressed in the context of recipient MHC molecules (indirect pathway). The role of the indirect pathway in the rejection process remains poorly understood although some evidence suggests that these T cells may be important mediators of both acute and chronic rejection. In order to better elucidate the role of indirect allorecognition in allograft rejection, the investigators have isolated and characterized a CD4+ TH1 T cell line (SH10) from recipient BALB/c mice that specifically recognizes a single immunodominant allopeptide, (I-Abk 58-71, I-Ap), derived from the MHC II I-Ak molecule expressed on B10.A (H-2a) donor cells. When adoptively transferred into BALB/c SCID recipients of B10.A skin allografts, this cell line induces graft rejection characterized histologically by infiltration with SH10 T cells and macrophages. In this application they propose to extend this work to evaluate the role of the direct and the indirect pathway as mediators of acute and chronic rejection of vascularized organs, and to begin to evaluate the mechanisms of rejection initiated by indirect allorecognition. They propose to fully characterize T cell lines and clones reactive to direct and indirect pathway alloantigens. The applicants will then adoptively transfer these cells into SCID recipients of skin and heterotopic cardiac allografts in order to determine whether they are capable of mediating acute rejection. They will then test the role of macrophages in the development of allograft rejection induced by direct and indirect pathway allorecognition through adoptive transfer of cell lines into macrophage depleted SCID recipients of allografts. Finally they will test whether T cells reactive to antigens presented by the direct and the indirect pathway can induce chronic rejection of heterotopic cardiac and aortic allografts in similarly designed adoptive transfer experiments. The findings resulting from this work will provide new insight into the mechanisms of both acute and chronic allograft rejection, and may provide the basis for novel approaches for the prevention of graft rejection in humans.
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