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Andrew W. Taylor, Darren J. Lee, Norikuni Kawanaka, Michail Sitkovsky, Akio Ohta; Immune Homeostatic Mechanisms Suppress Experimental Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2262.
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The rodent models of uveitis demonstrate that left untreated the ocular microenvironment reimposes immunosuppression and resolves uveitis. This may be possible because the ocular microenvironment promotes mechanisms of immune homeostasis. Two possible homeostatic pathways are the hypoxia-adenosinergic (H-A) pathway mediated by adenosine through A2A receptors (A2Ar) on T cells, and the melanocortin pathway mediated by α-MSH. The two pathways are linked through the activation of HIF-1α. Therefore, we assessed whether it is possible to engage the H-A pathway during uveitis, and assess if any α-MSH activity requires HIF-1α activation.
C57BL/6 mice were immunized with IRBP to induce experimental autoimmune uveitis (EAU). The mice were injected i.p. three times either at the start or during the chronic phase of uveitis with A2Ar agonist GCS21680 (GCS). Fundus exams were conducted, and the retinitis was scored. Spleen cells were collected to assay IRBP-specific T cell production of IFN-γ, IL-17, and TGF-β. The apoptotic program was activated in macrophages to assess their rescue by α-MSH with the addition of HIF1α-inhibitor, and incubated for 24 hours. The cells were assayed for viability, and by TUNEL staining.
The clinical scores of EAU were significantly suppressed regardless of when GCS was injected and remained suppressed. The recovery from EAU was no different in the mice GCS injected at the onset of EAU compared to a PBS injected control, but was significantly accelerated in the mice GCS injected at the start of the chronic phase of EAU. Along with the accelerated recovery was an early induction of IRBP-specific Treg cells in the mouse spleens. In addition, macrophages could not be rescued from apoptosis by α-MSH in the presence of HIF1α-inhibitor.
The H-A pathway can be engaged during uveitis to suppress the severity, and to accelerate the resolution of autoimmune uveitis. In addition, α-MSH mediated ocular immunomodulation may also function through the H-A pathway. These results imply that the mechanisms of ocular immune privilege include normal immune homeostatic pathways.
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