1 / 8

Experimental autoimmune uveitis as a model of human uveitis

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

corinne
Download Presentation

Experimental autoimmune uveitis as a model of human uveitis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Experimental autoimmune uveitis as a model of human uveitis

  2. 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 targetingagents (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

  3. 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

  4. 0 2 4 6 19 21 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 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 // Fundoscopy Histology Normal EAU 2–3+

  5. Human: Normal fundus Ocular Sarcoidosis Mouse: Normal fundus Uveitic fundus Murine EAU vs. uveitis - clinical and histology Normal mouse retina EAU in mouse Ocular Sarcoidosis

  6. 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

  7. EAU vs human uveitis: similarities and differences EAUUveitis Triggering event induced “spontaneous” Reactivity to retinal Ag immunizing Ag S-Ag, IRBP, recoverin Clinical course acute or chronic usually chronic Pathology chororoiditis yes Yesretinitis Yes yes subretinal neovasc some someiridocyclitis 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

  8. 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 Immunology21:67-88, 2002. Caspi RR. Regulation, counter-regulation, and immunotherapy of autoimmune responses to immunologically privileged retinal antigens. Immunol Res. 2-3):149-60 (2003).

More Related