April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Experimental Autoimmune Uveitis in Mice With Defective Th1 and Th17 Effector Responses
Author Affiliations & Notes
  • J. Damsker
    Immunology, National Eye Institute, Bethesda, Maryland
  • D. Luger
    Immunology, National Eye Institute, Bethesda, Maryland
  • P. Silver
    Immunology, National Eye Institute, Bethesda, Maryland
  • C.-C. Chan
    Immunology, National Eye Institute, Bethesda, Maryland
  • Y. Iwakura
    Molecular Pathogenesis, University of Tokyo, Tokyo, Japan
  • R. Caspi
    Immunology, National Eye Institute, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  J. Damsker, None; D. Luger, None; P. Silver, None; C.-C. Chan, None; Y. Iwakura, None; R. Caspi, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 3809. doi:
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      J. Damsker, D. Luger, P. Silver, C.-C. Chan, Y. Iwakura, R. Caspi; Experimental Autoimmune Uveitis in Mice With Defective Th1 and Th17 Effector Responses. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3809.

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

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Purpose: : Experimental autoimmune uveitis (EAU) induced in mice by immunization with the uveitogenic retinal antigen IRBP is a model for autoimmune uveitis in humans. Recently, we showed that Th1 and Th17 responses are fully redundant for induction of EAU and can substitute for each other. This study examines the effect of deficiency in both the Th1 and the Th17 signature cytokines, IFN-γ and IL-17, on susceptibility to EAU.

Methods: : We generated IL-17/IFN-double knockout (DKO) mice on the C57BL/6 background. DKO mice and their WT and single KO controls were challenged for EAU by immunization with IRBP. Disease development was assessed by histology and fundoscopy, and cytokines in extracts of inflamed eyes were measured by ELISA, intracellular cytokine staining and quantitative RT-PCR. Some mice were given neutralizing anti-TNF-α antibody every other day during the effector phase of disease.

Results: : Despite lack of both IFN-γ and IL-17, the DKO mice developed full-blown EAU. They exhibited enhanced Th2 responses and undiminished production of IL-22 and proinflammatory cytokines such as IL-1 in response to IRBP at the systemic level. At the local level, DKO eyes showed strongly elevated Th2 transcription factors GATA-3 and c-Maf, Th2 cytokines such as IL-13 and IL-5, and eosinophil/granulocyte attracting chemokines. In keeping with this, histological analysis of diseased eyes uncovered a granulocytic/eosinophilic infiltrate in the DKO mice that is in contrast to the lymphocytic/monocytic infiltrate typically seen in wild type mice. Similarly to WT mice, EAU in DKO mice was inhibited by treatment with a neutralizing Ab to TNF-alpha.

Conclusions: : Taken together, these findings suggest the presence of a pathogenic, autoimmune effector response with Th2-like characteristics that develops in the concurrent absence of IFN-γ and IL-17. TNF-α remains a pathogenic cytokine in this model. Further studies using neutralizing Abs to other expressed cytokines or their receptors will address their role in pathogenesis.

Keywords: inflammation • uveitis-clinical/animal model • cytokines/chemokines 

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