April 2011
Volume 52, Issue 14
ARVO Annual Meeting Abstract  |   April 2011
Deficiency of IFN-gamma Delays the Onset of Spontaneous Uveitis in IRBP T cell Receptor Transgenic Mice
Author Affiliations & Notes
  • Jun Chen
    Lab of Immunology,
    National Eye Inst/NIH, Bethesda, Maryland
  • Reiko Horai
    Lab of Immunology, National Eye Institute, Bethesda, Maryland
  • Phyllis B. Silver
    National Eye Institute, National Institute of Health, Bethesda, Maryland
  • Chi-Chao Chan
    Immunopathol Section, Lab of Immunology, National Eye Institute/NIH, Bethesda, Maryland
  • Rachel R. Caspi
    Laboratory of Immunology,
    National Eye Inst/NIH, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  Jun Chen, None; Reiko Horai, None; Phyllis B. Silver, None; Chi-Chao Chan, None; Rachel R. Caspi, None
  • Footnotes
    Support  NIH's Intramural Program
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2947. doi:
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      Jun Chen, Reiko Horai, Phyllis B. Silver, Chi-Chao Chan, Rachel R. Caspi; Deficiency of IFN-gamma Delays the Onset of Spontaneous Uveitis in IRBP T cell Receptor Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2947.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Our previous studies revealed the dual effect of IFN-γ in experimental autoimmune uveitis (EAU). IFN-γ is protective in EAU induced by immunization with IRBP. Conversely, however, IFN-γ is required for disease induction in EAU induced by IRBP-pulsed dendritic cells, and adoptively transferred polarized Th1 cells (IFN-γ-producing) are highly pathogenic. To investigate the role of IFN-γ in the pathogenesis of uveitis, we used a newly developed spontaneous EAU model in IRBP T cell receptor transgenic (TCR Tg) mice crossed onto an IFN-γ knockout background (GKO).

Methods: : IRBP TCR Tg mice were generated on the EAU-susceptible B10.RIII background. GKO mice were backcrossed onto the B10.RIII background, and then crossed to IRBP TCR Tg mice (Tg-GKO). IRBP-specific T cells were detected using IRBP161-180/I-Ar/IgG1 dimers. Disease was evaluated by fundoscopy and histology. Lymphocyte proliferation was measured by [3H]-Thymidine incorporation. Cytokine levels were determined by ELISA or by flow cytometry with intracellular staining.

Results: : Lymphocytes of Tg-GKO mice contained similar frequency of IRBP-specific T cells, as judged by antigen-specific dimer reagent, and showed comparable proliferative responses to IRBP peptide to their IFN-γ-sufficient TCR Tg littermates. Upon IRBP peptide stimulation, Tg-GKO lymphocytes did not produce IFN-γ, as expected, and instead produced high amounts of IL-17A. Most Tg-GKO mice developed spontaneous uveitis between 6 weeks and 4 months of age, whereas most IFN-γ-sufficient TCR Tg mice had detectable disease at 3 weeks and virtually all had uveitis by 2-3 months of age. In addition to delayed disease onset, Tg-GKO mice also showed decreased severity scores compared to their IFN-γ-sufficient IRBP TCR Tg counterparts.

Conclusions: : Although IFN-γ appears to be dispensable for development of spontaneous EAU, delayed onset and reduced scores of disease in Tg-GKO mice point to a pathogenic role for this cytokine, that is not compensated for by increased levels of IL-17A.

Keywords: autoimmune disease • cytokines/chemokines • immunomodulation/immunoregulation 

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