Intestinal transplantation is a potential definitive therapy for short bowel syndrome. This condition, which can result from a number of intestinal diseases, at the present time is not curable, but can be palliated with total parenteral nutrition, a therapeutic modality that has an unacceptable long-term morbidity. To identify the clinical potential for intestinal transplantation, we are planning to study intestinal transplantation in a preclinical animal model using histoincompatible donor/recipient strains of rats. The technique will first be optimized using syngeneic donors and recipients. We will then attempt to improve graft survival using Cyclosporine as an immunosuppressant and attempt to induce specific transplantation tolerance, using total lymphoid irradiation with and without the help of Cyclosporine. Once the model of intestinal transplantation between syngeneic and allogeneic donor/recipient pairs has been firmly established, we will study the immunobiological patterns of transplanted intestine using histologic and functional tools including biopsy, immunohistology, assay of maltose absorption, measurement of serum levels of the mucosal enzyme diamine oxidase, and nuclear imaging to detect retention of intraperitoneally injected Xe-133. We will study intestinal grafts in untreated and Cyclosporine-treated parent/hybrid and hybrid/parent donor/recipient combinations. These studies should establish definitive criteria to differentiate between rejection and graft-versus-host disease. Utilizing these data, the immunobiological patterns in strictly allogeneic histoincompatible donor/recipient combinations will be defined. We hope by this experiment to detect signs of rejection or graft-versus-host disease early enough to permit treatment without risk to the life of the recipient. These studies should lead to the development of preparatory regimens that permit long-term survival and possibly immunological tolerance of intestinal grafts. In the last section of the proposed research we will try to identify the mechanism or mechanisms that underlie the development of tolerance, by a mature organism, of a grafted, immunocompetent solid organ like the intestine. In this section, we will try to ascertain if clonal deletion is responsible for tolerance, if suppressor phenomena can be identified, or if immunobiologically specific transplantation tolerance cannot be established under these circumstances.
