Age-related macular degeneration (AMD) is a major cause of blindness in the United States. Replacement of dead or damaged cells with healthy retinal cells is a very promising approach to the treatment of this, and other, retinal diseases. Our long-term goal is to develop the methods for transplanting retinal pigment epithelial (RPE) cells early in the course of AMD to rescue photoreceptor cells. The central hypothesis of this proposal is that the identification of the immunological mechanisms, which are responsible for RPE transplant rejection, will provide therapeutic targets for inducing long-term graft acceptance. ? The role of CD4+ and CD8+ T cells in rejection will be tested by adoptively transferring them into ? immunodeficient, recombinase (Rag-1) knockout mice before transplantation of allogeneic RPE. The relative contribution of major and minor histocompatibility antigens to RPE rejection will be assessed using recombinant, inbred strains of mice. The mechanisms by which RPE grafts are rejected will be determined using T cell receptor (TCR) transgenic mice and RPE expressing defined transplantation antigens. Activation and proliferation of adoptively transferred TCR transgenic T cells will be tracked in lymph nodes and the eyes of transplant recipients. TCR T cells recovered from the eyes will be analyzed for various functional activities. Finally, the hypothesis that allograft-specific tolerance can prolong survival of RPE in the absence of continuous treatment with immunosuppressive agents will be tested. ? Results from these studies should identify strategies to prevent rejection that can be tested in preclinical models of RPE transplantation. ? ?
