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. EAU in rodents, similarly to uveitis in humans, is genetically controlled. EAU is dependent on MHC as well as on non-MHC genes. While MHC dependence is easy to conceptualize as primarily reflecting epitope recognition, non-MHC mechanisms are complex. Cytokine response patterns play an important role in determining susceptibility. The ability to produce interleukin 12 (IL-12), an innate cytokine that drives Type 1 inflammatory responses, is required to develop EAU. Mice deficient in IL-12 are unable to develop EAU by immunization with a retinal antigen because they cannot generate the Th1-like pathogenic effector T cell. Susceptible strains of rodents display dominant Type 1 responses at the time of disease expression. Resistant rodents show either a dominant Type 2 pattern, or a pattern low in Type 1 cytokines. Interestingly, the response in both resistant and susceptible strains is initially more reminiscent of a Type 0 response, which subsequently polarizes towards Type 1 or Type 2 in susceptible and resistant strains, respectively. A genome-wide analysis of loci associated with EAU, performed in F2 progeny of susceptible Lewis and resistant F344 rats, revealed two genomic regions, located on chromosomes 4 and 12, with strong linkage to the EAU phenotype. Based on chromosome synteny with the mouse, these regions are expected to contain a number of immunologically relevant genes. These regions appear to be associated also with some other autoimmune diseases. Alleles of such loci could be responsible for familial clustering of several autoimmune diseases in humans. In a study designed to test cytokine-based therapeutic approaches to EAU, we examined the role of IL-10 in regulation of EAU by studies that employed in vivo neutralization, as well as augmentation, of IL-10. Mice treated with exogenous IL-10 were protected from EAU and had a reduced Th1 response. These data indicated that endogenous IL-10 participates in natural regulation of the disease, and that treatment with recombinant IL-10 is a feasible approach to therapy of uveitis. In another study we found that a state of pregnancy, which was demonstrated in some other experimental systems to upregulate Type 2 responses and limit Type 1 responses, protected mice from induction of EAU. Inhibition of EAU was associated with downregulation of Th1 responses to the uveitogenic antigen, with only minimal upregulation of Th2 responses, but with a significant upregulation of the immunosuppressive cytokine TGF-beta in the serum. These data may explain the observation why uveitis patients tend go into temporary remission during pregnancy. These data also support the concept that shifting the response away from Type 1 represents a viable therapeutic approach in uveitis.
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