Abstract
Purpose :
The melanocortin system plays a vital role in regulating immune activity and retinal cell health within the eye. Augmenting the melanocortin system with α-melanocyte stimulating hormone (α-MSH) during uveitis suppresses inflammation, promotes immune tolerance, and protects the retinal structure. To determine which melanocortin-receptors are important in mediating the beneficial effects of α-MSH-therapy, we assayed different α-MSH-analogs with different functional melanocortin-receptor (MC1r, MC3r, MC4r, and MC5r) specificities.
Methods :
Experimental autoimmune uveitis (EAU) was induced in C57BL/6J mice, and the retinas were clinically scored by fundus exam. When the mice reached the chronic stage of EAU, they were injected twice one-day apart with 50 µg of α-MSH (pan-agonist), PL8331 (pan-agonist), PL8177 (potent MC1r-only agonist), PL5000 (same as α-MSH but no MC5r functional activity), MT-II (same as PL5000) or PG901 (MC5r agonist, but an antagonist to MC3r, and MC4r). Clinical EAU scoring was continued until EAU resolution in the α-MSH-treated EAU mice. The eyes were then collected for histology, and spleen cells were collected for retinal-antigen-stimulated IL-17 and IL-10 production.
Results :
There was significant EAU suppression with significant retinal structure preservation in EAU mice treated with α-MSH and PL8331. A similar effect was seen in PL8177 treated EAU mice, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with no preservation of the retinal structure, The stimulated spleen T cells produced IL-10 in mice treated with α-MSH, PL8331, PL8177, PL5000, but continued to produce IL-17 in MT-II, and PG901 treated EAU mice.
Conclusions :
In this study, we investigated the effects of α-MSH-analogs in suppressing EAU. Our previous studies showed the importance of the melanocortins in the maintenance of ocular immune privilege and that α-MSH-treatment accelerated recovery and induced retinal-antigen-specific regulatory immunity. Our current results demonstrated that α-MSH-analogs targeting MC1r and MC5r together have a therapeutic potential to suppress uveitis and induce regulatory immunity. Moreover, they can maintain normal retinal structure and prevent retinal cell loss.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.