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Lindsey F. Nugent, Guangpu Shi, Barbara P. Vistica, Cuiyan Tan, Igal Gery; A Novel Nontoxic Aryl Hydrocarbon Receptor Ligand, ITE, Suppresses Immune-mediated Ocular Inflammation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2759.
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© ARVO (1962-2015); The Authors (2016-present)
Stimulation of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) by its ligands suppresses autoimmune diseases by interfering with the activation of Th1 and Th17 cells and expanding CD25+Foxp3+ Treg cells. Previously tested AHR activators were highly toxic and not suitable for clinical use. Recently, an endogenous nontoxic AHR ligand, designated ITE, became available and was reported to carry immunosuppressive capacity. Here, we investigated the suppressive effects of ITE on the induction of experimental autoimmune uveitis (EAU), a model of uveitis in humans, and immune response against the uveitogenic antigen.
B10.A mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) in CFA emulsion and concurrently injected with pertussis toxin. Treatment with ITE, 200 μg, or PBS as control, was administered daily. Development of EAU was evaluated by fundoscopy on day 12 post-immunization and by histological examination on day 14. Draining lymph node cells were collected and used for (i) analysis of Foxp3 expression, by intracellular staining, or (ii) cultured with IRBP to measure proliferative response and cytokine secretion. Serum antibody to IRBP was measured by ELISA.
Both clinical and pathological evaluations revealed that ITE suppressed EAU. Additionally, ITE suppressed the T-cell recall proliferative response to IRBP, and decreased the secretion of the pro-inflammatory cytokines IFNγ and IL-17. Surprisingly, however, treatment with ITE also reduced the release of the immunoregulatory IL-10. Treatment with ITE increased the proportion of Foxp3+ T-cells, but just marginally. In addition, ITE treatment slightly decreased the antibody response.
Treatment with the nontoxic endogenous AHR ligand, ITE, suppresses the development of EAU and cellular responses to the uveitogenic antigen. Thus, ITE is a potential new compound for the treatment of autoimmune disorders.
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