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C. Yu, Y. Lee, R. Mahdi, J. Burton, C. E. Egwuagu; Therapeutic Targeting of Stat3 Pathways in Autoimmune Inflammatory Disease of the CNS. Invest. Ophthalmol. Vis. Sci. 2010;51(13):815.
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Mice with targeted-deletion of STAT3 in CD4+ T-cells do not develop EAU or EAE because of their inability to generate pathogenic Th17 cells (J. Immunol. 180:6070). Loss of STAT3 in T cells also interfered with expression and activation of α4 (CD49d) and β1 (CD29) integrins and prevented trafficking or entry of Th1 or Th17 cells into the eyes. These observations suggest that STAT3 is an attractive therapeutic target that can be used to inhibit uveitis or multiple sclerosis. Here, we investigated the efficacy of chemical inhibitors of STAT3 as potential drug for the treatment of uveitis.
ORLLNIH001 is a synthetic small chemical compound that has been shown to be a selective inhibitor of STAT3 in pre-clinical models of oncology. We induced experimental autoimmune uveitis (EAU) in B10A mice by immunization with IRBP in CFA. We also administered ORLLNIH001 intravenously starting 1 day before immunization. For some mice, drug treatment commenced 5 days post-immunization. For all groups, ORLLNIH001 was administered every other day until post-immunization day 17. Development and severity of EAU were assessed by fundoscopy and histopathology. Phenotype of lymphocytes in lymph nodes and PBMC was characterized by FACS and intracellular cytokine staining assay. We also performed a comparative analysis of ORLLNIH001 and other commonly used anti-inflammatory drugs in terms of their inhibitory effects on human PBMC.
We show that ORLLNIH001 reduced the severity of EAU as indicated by marked reduction in retinal folds and inflammation. The inhibitory effects were observed not only in mice that received the drug 1 day before immunization but also those that received ORLL 5 days post-immunization. These results, suggest that while ORLLNIH001 is able to limit the disease progression, it does not prevent development of EAU. Analysis of T cells in draining lymph nodes and PBMC revealed that ORLLNIH001 inhibited expansion and recruitment of T cells into the eye. Importantly, ORLL inhibits expansion of Th17 cells in human PBMC, underscoring its potential as drug for treatment of human inflammatory diseases. ORLL differs from other anti-inflammatory drugs such as cyclosporine, FK506 and steroids in that it selectively targets Th17 and therefore potentially beneficial for treatment of IL-17-induced chronic inflammatory diseases.
Chemical inhibitors of STAT3 are potential drugs for treating uveitis and other autoimmune diseases.
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