Regulation of JAK/STAT pathways in the eye

National Eye Institute

Investigators

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Abstract

Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases that includes Behcets disease, birdshot retino-choroidopathy, Vogt-Koyanagi-Harada disease, sympathetic ophthalmia, and ocular sarcoidosis. The etiology of uveitis is not fully understood but may be linked to autoimmunity. We previously identified the critical role of STAT3 transcription factor in regulating the development of Th17 cells that mediate uveitis and targeted deletion of STAT3 suppressed uveitis in mice. In this study, we developed a novel antibody (SBT-100) comprised of the variable (V) region of a STAT3-specific heavy chain molecule and demonstrate that this 15 kDa STAT3-specific nanobody enters human and mouse cells, induced suppression of STAT3 activation and lymphocyte proliferation in concentration dependent manner. We then investigated whether SBT-100 would be effective in suppressing experimental autoimmune uveitis (EAU). Analysis of EAU mice by fundoscopy, histological examination or optical coherence tomography showed that treatment with SBT-100 suppressed uveitis by inhibiting expansion of pathogenic Th17 cells that mediate EAU. Electroretinographic (ERG) recordings also showed SBT-100 treatment rescued mice from developing significant visual impairment. These observations were confirmed by adoptive transfer experiments, suggesting potential use of SBT-100 immunotherapy for human autoimmune diseases.