June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Suppression of uveitis with melanocortin receptor specific agonists
Author Affiliations & Notes
  • Andrew W Taylor
    Ophthalmology, Boston Univ School of Medicine, Boston, MA
  • David Yee
    Ophthalmology, Boston Univ School of Medicine, Boston, MA
  • Darren J Lee
    Ophthalmology, Boston Univ School of Medicine, Boston, MA
  • Footnotes
    Commercial Relationships Andrew Taylor, Mallinckrodt (Questcor) Pharmaceuticals (C), Mallinckrodt (Questcor) Pharmaceuticals (R), Palatin Technologies (C), Palatin Technologies (F), Palatin Technologies (R); David Yee, None; Darren Lee, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3205. doi:
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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)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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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