T CELL Costimulation in Intestinal Allograft Rejection

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DESCRIPTION: (Verbatim from the applicant's abstract) Transpiantation is definitive therapy for many types of organ failure. However, results of intestinal transplantation are inferior to other transplanted organs due to the unique severity of intestinal rejection. To understand the factors responsibk hr this unusually severe rejection the results of intestinal and cardiac transplantation in mice were compared. CD8 T cells, while not sufficient for rejection of cardiac allografis, were sufficient to reject intestinal allografts. This observation highlights the important role that CD8 T cells can play in allograft rejection and demonstrates that the differing immunogenicity of cardiac and intestinal allografis is at least in part due to different mechanisms ofrejection. These data illustrate the need to identify immunosuppressive agents that inhibit CD8 T cells. The murme intestinal transplant model is an excellent tool for both this purpose and to study the immunobiology of CD8 T cells in vivo. Blockade of T cell costimulatory signals has been shown to prevent rejection in several experimental models. However, although blockade )f the CD28/B7 or CD154/CD4O costimulatory pathways using CTLA4Ig or MR1 prevented rejection of cardiac allografts, it did not inhibit rejection of intestinal allografls. Importantly, both agents inhibited intestinal allograft rejection by CD4, but not CD8, T cells. These data provide direct evidence of the differing costimulatory requirements of CD4 anc CD8 T cells in vivo. New data show that CD8 T cell-mediated rejection was inhibited in short-term experiments by LTbRIg, an agent that blocks both T cell costimulation and dendritic cell maturation and migration. The FIRST SPECIFIC AIM is to identify agents that result in the long-term inhibition of CD8 or CD4 T cell-mediated rejection in vivo. Combinations of these agents will then be tested in wild-type mice in an attempt to design a clinically applicable immunosuppressive regimen. Reagents tested will include monoclonal antibodies and fusion proteins that block the CD28/B7, CD! 54/CD4O, and newly described LIGHT-LT/HVEM-LTR costimulatory pathways. The SECOND SPECIFIC AIM is to determine the mechanism by which these agents inhibit the function ofCD8 and CD4 T cells and prevent allograf rejection. The function of cells from treated mice will be determined in vitro and in vivo. These studies will also provide information about the requisite events necessary for T cell activation and the development of effector function. The THIRD SPECIFIC AIM is to define the relative importance of the direct and indirect pathways of antigen presentation anc costimulation during allograft rejection. Using the ELISPOT assay, MUC and dendritic cell deficient mice, and TCP transgenic mice the roles of the direct and indirect pathways in rejection will be determined for both CD8 and CD4 T cells.