The major objectives of this proposal are to continue studies on the prevention of rejection of adult islet allografts in rodents, adult islet allografts in rodents without the continuous use of immunosuppressive drugs in the recipients. We have shown that rejection of islet allografts in mice can be prevented by in vitro treatment of donor mouse islets with a specific Ia antibody or a monoclonal antibody to mouse dendritic cells and complement and preimmunization of recipient mice with donor blood depleted of Ia+ cells. We have shown that rejection of islet allografts in rats can be prevented by low temperature culture (24 C) and a single injection of ALS into the recipient. We will attempt to prevent rejection of rat islet allografts by treatment of donor islets with cross-reactive Ia antibodies or by monoclonal antibodies to rat dendritic cells. Studies are also in progress to determine whether specific suppressor lymphoid cells have been induced in mice bearing established islet allgrafts. A model has been developed for the induction of T suppressor cells inhibiting the in vitro generation of cytotoxic T lymphocytes by treatment of mice with cyclosporin A and allogeneic spleen cells. This model will be tested for prevention of rejection of islet allografts and xenografts. We have shown that xenografts across a closely related species barrier (rat to mouse) can be prevented from rejecting by low temperature culture and a single injection of ALS. We will determine whether xenografts of islets transplanted across a wide species barrier (beef, dog, pig or hamster to rat or mouse recipients) can be prevented from rejecting using the procedures that have prevented rejection of islet allografts in rodents. The procedures that we have developed for prevention of rejection of adult islet allografts will also be used to determine whether these methods will prevent rejection of fetal pancreas allografts. These investigations on preventing rejection of islet allografts and xenografts without using immunosuppressive drugs are of importance to utilizing islet transplantation in human diabetes and the transplantation of other tissues and organs.
| Goss, J A; Finke, E H; Flye, M W et al. (1994) Induction of immune unresponsiveness to concordant islet xenografts by intrahepatic preimmunization and transient immunosuppression. J Clin Invest 93:1312-4 |
| Goss, J A; Nakafusa, Y; Finke, E H et al. (1994) Induction of tolerance to islet xenografts in a concordant rat-to-mouse model. Diabetes 43:16-23 |
| Holers, V M; Hollis, G F; Schwartz, B D et al. (1993) Induction of peri-insulitis but not diabetes in islet transplants expressing a single foreign antigen. A multi-stage model of disease. J Immunol 151:5041-52 |
