INTESTINAL ALLOGRAFT REJECTION--MECHANISMS AND THERAPIES

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DESCRIPTION (Adapted from applicant's abstract): Although allograft rejection remains an obstacle for all organ transplants, the high incidence and severity of rejection following intestinal transplantation is the major factor limiting the uniform successful clinical application of this procedure. This research proposal is based on the hypothesis that rejection of intestinal allograft is qualitatively different from that of other organs. The investigators have developed a novel model of mouse intestine transplant to test this hypothesis, allowing them to utilize well-defined biological reagents and transgenic strains available only for this species. Their preliminary observation is that, distinct from previously described animal models of other organ transplants, CD8 T cells play a critical and essential role in the rejection of the intestine, using in vivo monoclonal antibody depletion studies. They will characterize the involvement of CD8 T cells in the rejection of the intestine and compare the role of CD8 cells in the intestine to heart transplant rejection. In the second observation, they have shown that mice genetically deficient in CD8 T cells retain the ability to reject intestine transplant. They will examine the mechanism by which treatment with anti-CD8 monoclonal antibodies prolong survival of intestinal allografts and contrast this to the mechanism used by CD8 knockout mice to reject similar grafts. Finally, they will take advantage of their model to study the unique role that CD8 T cells play in rejection in vivo. They will directly examine the costimulatory requirements and functional properties of CD8 T cells in mediating allograft rejection.