Experimentalautoimmuneuveitisasamodelofhumanuveitis.pptVIP

Experimental autoimmune uveitis as a model of human uveitis Human autoimmune uveitis Intraocular inflammation without an infectious etiology, considered to be autoimmune Strong MHC associations Patients exhibit immunological responses to retinal antigens Improvement with T cell targetingagents (CsA, rapamycin, anti-IL-2R) ~ 70,000 cases/yr Affected age group 20-40 yo Account for ~10% of blindness in the US Experimental autoimmune uveoretinitis (EAU) An animal model used to represent human immune mediated / endogenous uveitis Induced by immunization with purified retinal antigens S-Ag (arrestin), IRBP, rhodopsin/opsin, phosducin, recoverin Responses to these antigens are seen in some uveitis patients Inducible in a variety of species Mouse, Rat, Guinea Pig, Rabbit, Monkey Pathological manifestations resemble human uveitis Experimental autoimmune uveoretinitis (EAU) in mice: a model for human autoimmune uveitis IRBP (Interphotoreceptor retinoid-binding protein) ? 140 KD, 4 domains, conserved? Unique to eye? Functions in retinoid transport Quantitation of disease: Scored on a scale of 0 – 4, according to number and size of lesions. Strain dependence of susceptibility B10.RIII, B10.A - susceptible AKR, BALB/c - resistant Murine EAU vs. uveitis - clinical and histology Cellular mechanisms in EAU T cell dependent: Transferred from immunized donors to normal recipients by T cells, but not by serum (although antibodies when present can modify the course of disease) Pathogenic T cell has a Th1-like phenotype Susceptible individuals are genetically predisposed to a Th1 response Long-term T cell lines specific to retinal antigen transfer disease without formation of detectable serum antibodies Disease suppressed or reversed by pharmacological T cell-targeting agents, e.g., CsA, rapamycin, anti-IL-2R Ab Amenable to regulation by Ag-specific genetic therapies through induction of peripheral tolerance IL-10 has a negative regulatory role EAU vs human uveitis: si