Cytolytic T lymphocytes (CTL) are major effectors of clinical allograft rejection in patients treated with calcineurin inhibitor-based immunosuppression and graft endothelial cells (EC) are major targets of CTL-mediated injury. Moreover, some CTL recovered from rejecting allografts are specific for EC and not other graft, cell types suggesting that such CTL arise in response to stimulation by graft EC. The investigators believe that improvements in post-transplant therapy should target those mechanisms least well controlled by current therapy, ie., CTL-mediated EC injury by either EC-selective or conventional MHC-restricted CTL, and that such improvements will depend on better understanding these mechanisms. This proposal (1) will investigate mechanisms utilized by EC to influence CTL maturation as well as the effects of modifying human EC, e.g., by cytokine treatments or gene transduction, on this process;will examine the role of adhesion molecules in the molecular basis of EC-selectivity;will compare the effects of adoptive transfer of EC-selective vs. conventional CTL in our huPBL-SCID/bg mouse models of allograft rejection;and will compare the phenotypes of EC-selective vs. conventional CTL using microarrays to develop biomarkers in order to identify EC-selective CTL in rejecting tissues generated both in huPBL-SCID/bg mouse models of allograft injury and in clinical biopsy specimens;(2) will determine the death pathways activated within human EC in response to EC-selective and to conventional CTL in culture and in biopsy specimens and identify strategies to block these responses;and (3) will investigate the mechanisms by which treatment with IL-11 or erythropoietin protect EC from CTL, paying particular attention to the role of STATS signaling. We will use microarrays to identify novel protective molecules. These data will provide a rational basis for developing new, complementary strategies to further reduce the incidence and consequences of allograft rejection.
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