The overall objective of this project is to define the role of renal microenvironment in alloimmune responses. The hypotheses to be tested are that the microenvironment of a kidney allograft will determine the intensity of the infiltrating population of T cells and that the metabolism of heparan sulfate and eicosanoids will contribute to that microenvironment. The number of T lymphocytes responding to an allogeneic kidney graft will be determined by morphometric analysis as well as a direct quantitation of allogeneic DNA. The intensity will be examined as a function of antigenic disparity using as allogeneic donors mice which have MHC class I or MHC class II or both classes of MHC antigens deleted via homologous recombination. The control of alloimmune responses will then be evaluated from the perspective of the metabolism of heparan sulfate and PGE2. The extent to which the metabolism of these substances in an allogeneic kidney graft determines the intensity and diversity of the cellular immune response will be tested. Toward the objective of manipulating the microenvironment, a method will be developed that will allow the transfer of recombinant DNA into an organ graft leading to alteration in the metabolism of heparan sulfate and thus potentially of eicosinoids. The effect of this manipulation on alloimmune response will be tested.
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