This is an application to characterize the molecular and cellular facets of host immunity in retinal transplantation. Retinal transplantation represents a promising approach for restoring sight to patients with diseases associated with irreparable damage to the retina. Recent evidence has been provided showing that both adult and neonatal retinal allografts placed in different compartments of the eye are immunogenic. In addition, some observations suggest that this immune response may accelerate deterioration of the graft. This indicates that, in patients with eye diseases associated with loss of immune privilege, disruption of blood ocular barrier and neovascularization, it is likely that retinal transplants will be rejected by the recipient immune system. Better understanding of the immune response induced after retinal transplantation in animal models may help designing strategies to solve this problem in the future. We hypothesize that 1) retinal allografts placed in the subretinal space induce both CD4+ and CD8+ mediated T cell responses, 2) retinal allografts induce both direct and indirect T cell mediated alloresponses, 3) alloresponse is initiated by the migration of MHC class 11+ cells out of the retina to host's lymphoid organs and, 4) anti-donor alloresponse contributes to the deterioration of retinal transplants. To examine the validity of these hypotheses, we propose to pursue three specific aims: 1. To characterize the lymphocytes activated after retinal allotransplantation, 2. To identify the cellular mechanisms involved in the immune responses to retinal allotransplants, and 3. To investigate the contribution of alloimmune response to retinal allograft deterioration in mice. Our study design relies on: the high sensitivity of three techniques, ELISA spot and immunoscope to characterize the frequency, phenotype, function, clonal expression of T cells activated after retinal transplantation, and MHC-RTPCR to measure the migration of donor cells from retinal allografts to the recipient's lymphoid organs. Our long-term objective: is to fully characterize the immune response to different portions (neuronal and pigment epithelium) of allogeneic retinas placed in the eye in health and disease. The overall health relevance of the proposed research is that transplantation of cells and tissues of the nervous system is currently being developed in the United States for patients with neurodegenerative diseases including Alzheimer disease, Multiple Sclerosis, macular degeneration. No information is currently available regarding the immunogenicity of these transplants and their susceptibility to immune-mediated destruction. Our project intends to fill this gap.
