Contributed by: Rachel R. Caspi, PhD, NEI, NIH ... Caspi

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Experimental autoimmune uveitis as a model of
human uveitis
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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
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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

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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
//
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
EAU 23
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Murine EAU vs. uveitis - clinical and histology
Normal mouse retina
EAU in mouse
Ocular Sarcoidosis
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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

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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 Yesretinitis Yes yes subretina
  l 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

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Suggested reading

• Caspi, R.R. Immune mechanisms in uveitis.
  Springer Sem. Immunopathol. 21113-124, 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 21197-208, 2002.
• Pennesi, G and R.R. Caspi. Genetic control of
  susceptibility in clinical and experimental
  uveitis. International Reviews of Immunology
  2167-88, 2002.
• Caspi RR. Regulation, counter-regulation, and
  immunotherapy of autoimmune responses to
  immunologically privileged retinal antigens.
  Immunol Res. 2-3)149-60 (2003).