Our broad, long term goal is to explore a new approach to immunosuppression in ocular disorders such as autoimmune diseases or allograft rejection. Allograft rejection is a major problem in corneal transplants and may also diminish the hope of using retinal pigment epithelial cell transplants to treat some degenerative eye diseases. As many as two thirds of the high risk corneal transplants fail due to rejection. The current immunosuppressive agents are indiscriminate and can broadly suppress immune functions; furthermore, after successful therapy, allograft reaction can recur. Consequently, we will investigate the feasibility of preventing allograft rejection in high risk animal corneal transplants utilizing interleukin 2 receptor (IL2-R) targeted immunotoxin therapy. The activation and expansion of a small population of the T-cells bearing T-cell receptors that recognize the alloantigens are crucial for allograft reaction. IL2-R is transiently expressed during the proliferative burst of antigen-sensitized lymphocytes; IL2-R expression is specific to activated lymphocytes and is not expressed by nonlymphoid cells, resting or memory lymphocytes. The specific elimination of this small population of alloimmune T-cells should render the host permanently immumo-unresponsive toward the allograft, without causing indiscriminate immunosuppression. IL2-toxin is a genetically engineered IL2-R targeted immunotoxin, derived from a diphtheria-related-polypeptide and human IL2. IL2-toxin is highly cytotoxic to both human and murine IL2-R (+) cells, and can abolish murine delayed type hypersensitivity reaction. Since IL2-R expression is a common pathway in T-cell activation, the specific elimination of IL2-R (+) cells by IL2-toxin should provide an utilitarian approach to achieve selective and long lasting immunosuppression. Utilizing rabbit corneal allograft model, we will determine the optimal modality of IL2-toxin treatment, and ascertain that IL2-toxin induced immunosuppression is long lasting and selective. After the therapeutic trials on the rabbit model, we will extend the study to monkeys, and utilize the anti-human lymphocyte monoclonal antibodies that are cross-reactive with monkey lymphocytes to investigate the roles of different types of IL2-R (+) cells in corneal allograft rejection and IL2-toxin induced suppression of allograft rejection.
