Experimental autoimmune uveitis as a model of human uveitis

Human autoimmune uveitis Normal human fundus Intraocular inflammation without an infectious etiology, considered to be autoimmune Strong MHC associations Patients exhibit immunological responses to retinal antigens Improvement with T cell targeting agents (CsA, rapamycin, anti-IL-2R) ~ 70,000 cases/yr Affected age group 20-40 yo Account for ~10% of blindness in the US Ocular Sarcoidosis ….fall into 2 broad categories…

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 Induction: Immunize with IRBP or adoptively transfer primed T cells (Th1) Onset: d 4-6 (cell transfer) or d 9-12 (immunization) Readout: day 14 (cell transfer) or day 21 (immunization) Assess EAU & responses // 2 4 6 19 21 Fundoscopy Histology 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 Normal The model we work in is EAU, that represents a number of blinding autoimmune uveitic diseases in humans where patients often have cellular responses to retinal antigens. Those same antigens induce EAU when used for immunization of animals This is what EAU looks like, this is the fundus of the healthy eye and a section through a healthy retina, and this is the eye of a mouse with uveitis - presence disease is easy to recognize. In this study we used IRBP, or interphotoreceptor retinoid binding protein whose role in life is to shuffle vitamin A derivatives between the photoreceptor, where it is made, and the retinal pigment epithelium. EAU is characterized by….etc. Susceptibility to EAU is strain dependent, which is important for the purpose of this presentation EAU 2–3+

Murine EAU vs. uveitis - clinical and histology Normal mouse retina Mouse: Normal fundus Uveitic fundus EAU in mouse Human: Normal fundus Ocular Sarcoidosis …Normal human eye in health and disease Ocular Sarcoidosis

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: similarities and differences EAU Uveitis Triggering event induced “spontaneous” Reactivity to retinal Ag immunizing Ag S-Ag, IRBP, recoverin Clinical course acute or chronic usually chronic Pathology chororoiditis yes Yes retinitis Yes yes subretinal neovasc some some iridocyclitis yes yes Genetic control MHC & background MHC (background?) MHC genes involved class II class I and class II Central role for T cells Yes (lines, clones) Yes (efficacy of T cell targeting treatments) Role of antibodies Modifying Suspected Can skip that as we have essentially covered much of it

Suggested reading Caspi, R.R. Immune mechanisms in uveitis. Springer Sem. Immunopathol. 21:113-124, 1999. Caspi, Rachel R. The Role of Cytokines in Induction and Regulation of Autoimmune Uveitis. In: Cytokines and Autoimmune Diseases, (V.K. Kuchroo, N. Sarvetnick, D.A. Hafler and L.G. Nicholson, Eds.). pp. 227-245, Humana Press, NJ, 2001 Gery, I., R.B. Nussenblatt, C.C. Chan and R.R. Caspi. Autoimmune diseases of the eye. in: The Molecular Pathology of Autoimmune Diseases, 2nd Edition, (A.N. Theophilopoulos and C.A. Bona,, editors). Taylor and Francis, New York, NY pp. 978-998, 2002 Caspi, RR. Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis. International Reviews of Immunology 21:197-208, 2002. Pennesi, G and R.R. Caspi. Genetic control of susceptibility in clinical and experimental uveitis. International Reviews of Immunology 21:67-88, 2002. Caspi RR. Regulation, counter-regulation, and immunotherapy of autoimmune responses to immunologically privileged retinal antigens. Immunol Res. 2-3):149-60 (2003).