experimental autoimmune uveitis as a model of human uveitis
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Contributed by: Rachel R. Caspi, PhD, NEI, NIH
Experimental autoimmune uveitis as a model of human uveitis
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
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
Human autoimmune uveitis Normal human fundus
Ocular Sarcoidosis
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
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
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
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 - susceptibleAKR, BALB/c - resistant
NormalNormal
EAUEAU2–32–3++
Fundoscopy Histology
Induction: Immunize with IRBP or adoptively transfer primed T cells (Th1)
Onset: d 4-6 (cell transfer) ord 9-12 (immunization)
Readout: day 14 (cell transfer) orday 21 (immunization)
Assess EAU & responses//
2 4 6 190 21
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
Murine EAU vs. uveitis - clinical and histology
EAU in mouse
Ocular Sarcoidosis
Normal mouse retina
Human: Normal fundus Ocular Sarcoidosis
Mouse: Normal fundus Uveitic fundus
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
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
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
EAU vs human uveitis: similarities and differences
EAU UveitisTriggering event induced “spontaneous”
Reactivity to retinal Ag immunizing Ag S-Ag, IRBP, recoverin
Clinical course acute or chronic usually chronic
Pathologychororoiditis yes Yesretinitis Yes yessubretinal 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
Contributed by: Rachel R. Caspi, PhD, NEI, NIH
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).
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