Retinal transplantation represents a reasonable approach for restoring sight to patients with irreparable damage to the retina. There are formidable barriers to successful accomplishment of retinal transplantation in the clinic. Among the barriers that must be overcome is the capacity of the immune system to recognize foreign tissues implanted within the eye and to cause their destruction. The field of transplantation immunology has reached a high level of knowledge about solid tissue grafts placed at conventional sites in the body, but the phenomenon of immune privilege in the eye renders it difficult to translate that knowledge directly to the benefit of retinal transplants. This application describes a series of experiments which explore critical issues in the immunobiology of intraocular retinal transplants: (1) the ability of microglia of graft-origin to function as passenger leukocytes and thereby dictate the immunogenicity of neuronal retinal grafts; (2) the status of immune privilege in the subretinal space, and its relation to immune privilege within the entire eye; (3) the extent to which neuronal retinal tissue and retinal pigment epithelium display the properties of immune privileged tissues; and (4) the nature of inflammatory/immune reactions within the subretinal space and the influence of these reactions on immune privilege and retinal graft survival in this space. While the entire set of experiments will be conducted in inbred strains of mice, the knowledge gained will have relevance to the human situation. The anticipated results of these experiments will lead to novel strategies that will enable (1) the reduction of the alloantigenic load and the immune vulnerability to rejection of neuronal retina and RPE grafts, and (2) the promotion of positive features of immune privilege of retinal tissues as well as the subretinal site of engraftment in order to secure allograft acceptance. Since immune/inflammatory and immunomodulatory cytokines and growth factors can act on retinal cells, a further hope is that the results obtained from the described experiments may also give insight into means by which these factors can be used to promote neurobiologic health among retinal grafts.
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