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 targeting agents (CsA, rapamycin, anti-IL-2R)
~ 70,000 cases/yr
Affected age group yo
Account for ~10% of blindness in the US
Ocular Sarcoidosis
….fall into 2 broad categories…

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. 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+

5. 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

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
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

8. Suggested reading
Caspi, R.R. Immune mechanisms in uveitis. Springer Sem. Immunopathol. 21: , 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 , 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 , 2002
Caspi, RR. Th1 and Th2 responses in pathogenesis and regulation of experimental autoimmune uveoretinitis. International Reviews of Immunology 21: , 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): (2003).