The goal of this proposal is to further understand how the neuropeptide alpha-melanocyte stimulating hormone (?-MSH) regulates immunity, and how it can be used to suppress uveitis to reestablish immune privilege. Previously published work, and the progress of our past grant-period demonstrated that ?-MSH-treatment during uveitis can restore immunosuppressive activity of retinal pigment epithelial cells (RPE). In addition, we have demonstrated that part of immune privilege is suppression of the phagocytic/antigen-processing pathway within macrophages by healthy RPE. This suppression is mediated by ?-MSH produced by RPE and is dependent on expression of the ?-MSH-receptor, melanocortin 5 receptor (MC5r), in the retina. Therefore, suppression of EAU, and the induction of regulatory T cells by ?-MSH-therapy is possibly associated with regulating antigen presenting cell activity within the uveitic eye. This would be mediated through ?-MSH binding specific melanocortin-receptors on the RPE and APC of the retina. Therefore, we hypothesize that ?- MSH regulates the processing and presentation of antigen within the immune privileged microenvironment, and that ?-MSH-therapy acts through this mechanism to suppress autoimmune uveitis. We will demonstrate this regulation by assessing the role of ?-MSH to regulate the phagocytic pathway in macrophages and microglial cells; by determining the ability of ?-MSH-treated APC to antigen-activate effector T cells; and assess the potential for ?-MSH to mediate innate-immune memory tolerance in macrophages. The ?-MSH- therapy will involve treating EAU with whole neuropeptide and specific melanocortin-receptor-agonists. The regulation of antigen uptake, processing, and presentation will be assayed on both tissue macrophages, and retinal microglial cells. Also, we will examine retinal microglial cells and ?-MSH-treated macrophages for expression of markers and activity associated with innate-immune memory tolerance. We will examine changes in this regulation in the initial stages of EAU as suggested by our preliminary data. Our proposed work will have a meaningful impact, because the results will provide new information about the molecular mechanisms of uveitis, and ?-MSH anti-inflammatory-activity. Also, it will define how melanocortin-based therapy can regulate antigen presentation and T cell activation by suppressing the central drivers of autoimmune disease.
Uveitis is the third leading cause of vision loss the US, and it affects many during their most productive working years. The standard approach for treatment has not changed in almost 60 years. It is our objective to find a way of using the very molecules that regulate inflammation within the healthy eye that stops uveitis, that is well tolerated, and that it will provide a long-term benefit to preserve vision.
|Taylor, Andrew W; Ng, Tat Fong (2018) Negative regulators that mediate ocular immune privilege. J Leukoc Biol :|
|Clemson, Christine M; Yost, John; Taylor, Andrew W (2017) The Role of Alpha-MSH as a Modulator of Ocular Immunobiology Exemplifies Mechanistic Differences between Melanocortins and Steroids. Ocul Immunol Inflamm 25:179-189|
|Wang, Eric; Choe, Yoona; Ng, Tat Fong et al. (2017) Retinal Pigment Epithelial Cells Suppress Phagolysosome Activation in Macrophages. Invest Ophthalmol Vis Sci 58:1266-1273|
|Lee, Darren J; Preble, Janine; Lee, Stacey et al. (2016) MC5r and A2Ar Deficiencies During Experimental Autoimmune Uveitis Identifies Distinct T cell Polarization Programs and a Biphasic Regulatory Response. Sci Rep 6:37790|
|Taylor, Andrew W (2016) Ocular Immune Privilege and Transplantation. Front Immunol 7:37|
|Lee, Darren J; Taylor, Andrew W (2015) Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs. J Leukoc Biol 97:1101-9|