This project is intended to provide the scientific background necessary for the development of a clinical program of small bowel transplantation. Because of the volume of lymphoid tissue present in small bowel and its accompanying mesenteric lymph nodes, small bowel is both the target for vigorous rejection and an initiator of graft vs host disease (GVH). The ability of the new immunosuppressive drug Cyclosporin A to prevent both rejection and GVH will be investigated in rat and dog models of heterotopic small bowel transplantation. In addition, the cellular mechanism of GVH will be investigated using an adoptive transfer model based on the """"""""B"""""""" rat, which is devoid of functional T cell mediated immune function. Parental to F1 hybrid small bowel transplants from B rats reconstituted with various subpopulations of T cells will be used for these investigations. Pathological examination of small intestinal transplants will utilize both light and electron microscopy. Nutritional function of transplanted bowel in the dog will be assessed using nitrogen balance studies, D-xylose absorption tests, fecal fat excretion, and measurement of growth. Small bowel transplants will be performed in puppies to determine the ability of transplanted bowel to support normal growth and development. Finally, electrophysiologic studies of transplanted intestinal epithelium will provide data on the effect of transplantation and immunosuppression on water, ion, and small molecule transport. Together these studies are expected to provide sufficient information to initiate human small bowel transplantation, which would be of potentially significant benefit to patients with short bowel syndrome secondary to massive surgical resection for mesenteric vascular disease, infarction from torsion, advanced inflammatory bowel disease, or multiple polyposis.
