Rejection of solid organ transplants is initiated by the recognition of cell surface proteins encoded within the major histocompatibility complex (MHC). The recognition of these alloantigen targets produces a vigorous immune reaction that results in graft dysfunction and injury through both MHC specific and non-specific mechanisms. For the kidney grafts, a direct relationship between specific donor-host MHC differences and the composition and intensity of the alloimmune response has not been established. Based on the hypothesis that the nature of the MHC disparity between donor and recipient will determine the character of the immune response in kidney transplant rejection, the objective of the current proposal is to examine the role of donor alloantigens in shaping the recognition and effector pathways which cause kidney allograft dysfunction and injury. These studies will use mice in which cell surface expression of MHC antigens has been precisely altered through homologous recombination in embryonic stem cells. To achieve the long term objective, three specific aims are proposed.
These aims consider the immune response to a kidney allograft in settings in which either expression of MHC antigens in donors, or T cell populations in recipients have been altered through gene targeting.
The specific aims of this proposal are: 1) To characterize the mechanisms of rejection of kidney allografts from donors which lack cell surface expression of MHC class II or all MHC antigens. (2) To define T cell receptor (TCR) VBeta chain utilization in rejecting mouse renal allografts and to compare the relative effective of donor class I and class II proteins in determining intra-graft TCR VB chain repertoire. (3) To define the characteristics of CD4-CD8+alpha/BetaTCR+ cells which are induced in MHC class I deficient mice following exposure to intact MHC class I antigens on a transplanted kidney. By studying mechanisms of renal allograft rejection in these settings, the aim of this project is to provide new diagnostic and therapeutic approaches to problems in clinical transplantation.
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