Cellular and molecular mechanisms involved in T cell-mediated autoimmunity affecting the retina are being studied. The questions are aimed at elucidating the development and maintenance of self-tolerance to retinal antigens, and defining the processes that lead to their pathological breakdown. The goal is to use this knowledge for designing novel and rational strategies for immunotherapy. The experimental approaches utilize the model of experimental autoimmune uveoretinitis (EAU) that resembles immune-mediated uveitic diseases in humans, and is induced in mice and rats by immunization with retinal antigens or their peptides. Our previous studies showed that the effector T cell is an interferon-gamma (IFN-gamma)-producing Th1-like cell and genetic susceptibility to EAU is connected to a predominant Th1 response. Using F2 hybrids of the EAU-susceptible Lewis (a high Th1 responder) rat with the EAU-resistant F344 rat (a low Th1 responder), we have detected a locus linked to markers on chromosome 4 that controls EAU susceptibility in F344 x LEW rats. The proximity of this locus and loci detected in other autoimmune diseases such as diabetes, thyroiditis and arthritis, suggests the existence of a single locus that contributes to a variety of autoimmune disorders. Alleles of such a locus could be responsible for familial clustering of several autoimmune diseases in humans. In another study we found that a state of pregnancy, which was demonstrated in some other experimental systems to limit Th1 responses, protected mice from induction of EAU. This was associated with downregulation of Th1 responses to the uveitogenic antigen, with minimal upregulation of Th2 responses. These data may explain why uveitis patients may go into remission during pregnancy, but their disease may rebound in the postpartum period. These data also support the contention that immunomodulation to deviate the response away from Th1 and towards Th2 represents a viable therapeutic approach. Nevertheless, analysis of the immunological responses and the pathogenesis of EAU in IFN-gamma-deficient (knockout) mice has revealed that the photoreceptor damage typical of uveitis occurs in these mice in the context of a deviant effector response. This indicates that non-Th1 pathways to pathogenesis exist, and underscores the need for caution in evaluating immune deviation therapies as a clinical approach to uveitis. Interestingly, administration of IL-12, known to promote the Th1 response, protected mice from EAU. Protection was shown to correlate with suppression of all (Th1 and Th2) responses to the uveitogenic antigen and induction of apoptosis in lymphoid tissues. Using gene knockout mice, the protective effect of IL-12 was shown to require the ability to produce IFN-gamma and to upregulate inducible nitric oxide synthase (iNOS). We conclude that IL-12 protects from EAU by causing systemic upregulation of IFN-gamma, which in turn induces iNOS and consequently NO production, triggering apoptosis of antigen-specific uveitogenic cells. These data reveal a new potential role of IL-12 and the pathways it controls in regulation of autoimmunity. Lastly, a transgenic mouse that expresses a retinal protein extraocularly has been produced and is being characterized to study the mechanisms of self-tolerance to proteins expressed in immune privileged sites such as the eye.
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