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).