SIGNIFICANCE OF IMMUNOLOGICAL SEQUESTRATION IN THE EYE

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DESCRIPTION (Adapted from applicant's abstract): An enduring question in ocular immunology regards the role of sequestration in maintaining the immune privilege of the retina. Sequestration refers to the passive immune tolerance that is due to antigens being located behind physiologic and anatomic barriers, especially in the nervous system. The retinal vascular endothelium and pigment epithelium have been proposed to inhibit afferent and efferent immune processes by forming barriers to lymphocytic perusal and leakage of proteins. In addition, class II MHC expression is limited in sequestered sites, further inhibiting productive T cell antigen receptor occupancy. Although recent investigations have revealed the presence of inducible mechanisms of active tolerance that could, in theory, provide immune privilege, their activity has not been demonstrated in unstimulated, normal hosts. That difference is the essence of this proposal: to understand ocular immune privilege in animals where active, ocular mechanisms have not been induced by injection of antigens or cytokines into ocular compartments. The applicant will analyze the role of sequestration by two strategies. One approach uses the differential expression of the bacterial antigen beta-galactosidase, in transgenic mice. The other approach uses retroviral gene transfer to produce systemic expression of a known uveitogenic antigen, arrestin or S-antigen (S-Ag), allowing the effect of exposing the immune system to a well-characterized, non-sequestered S-Ag to be assessed. These strategies provide well-controlled opportunities to address a fundamental question in ocular immunology, and enhance our understanding of immune mechanisms responsible for maintaining tolerance to otherwise uveitogenic retinal antigens.