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Andrew W Taylor, David Yee, Darren J Lee; Suppression of uveitis with melanocortin receptor specific agonists. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3205.
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© ARVO (1962-2015); The Authors (2016-present)
Injections of the neuropeptide alpha-melanocyte stimulating hormone (α-MSH) suppress experimental autoimmune uveitis (EAU). There are several melanocortin receptors (MCr) for α-MSH with each signaling for different functions in different immune cells. Therefore, using MCr specific agonists it is possible to define the anti-inflammatory activity of α-MSH in treating EAU.
EAU was induced in C57BL/6 mice immunized with a peptide of interphotoreceptor retinoid-binding protein (IRBP) in complete Freunds adjuvant followed by pertussis toxin injections. The retinas were examined by slit lamp microscopy every 2 - 3 days and scored for inflammation. When the mice showed the first symptoms of uveitis they were injected with either the MC1r agonist PNT-107, or the MC5r agonist PG901. Examination of the eyes was continued. When the EAU of the treated mice resolved, their spleen cells were assayed for IRBP stimulated cytokines (IL-2, IL-6, IL-10, IL-17, IFN-γ). For the PG901 treated mice their spleen cells were adoptively transferred to mice immunized for EAU to see whether the cells suppressed EAU. The retinas were examined histologically.
In mice treated with PNT-107 or PG901 there was a significant acceleration in resolving EAU. It was resolved within 15 days after treatment compared to the >80 days of untreated EAU mice. The IRBP-stimulated response by the spleen cells was different between the EAU mice treated with PNT-107 and PG901. The PNT-107 treated mice had a significantly suppressed T cell response. The PG901 treated EAU mice still had an IRBP-stimulated effector Th1/Th17 response; however, adoptive transfer of the stimulated cells suppressed EAU in recipient mice. The retinas of eyes treated with either agonist were structurally intact with no evidence of photoreceptor loss.
The treatment of EAU with α-MSH peptide results in suppression of inflammatory immunity with the induction of regulatory T cells. These actions of α-MSH are through two different melanocortin receptors with MC1r being mostly anti-inflammatory, and MC5r mediating regulatory immunity. While anti-inflammatory mechanisms, and prevention of future reactivation of uveitis may be dependent on the specific melanocortin receptors, both agonists were highly effective in rapidly suppressing uveitis.
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