The eye normally possesses a unique physiological adaptation that regionally modifies the expression of immunity. This physiological adaptation is part of ocular immune privilege. The physiological role of immune privilege is to impart upon the eye immune protection that avoids the destructive side effects of immunogenic inflammation. Immunogenic inflammation associated with delayed hypersensitivity reactions can grossly distort the visual axis resulting in blindness. Consequently, immune protection within the eye involves a selective deficiency of delayed type hypersensitivity T-cells. To control immunogenic inflammation, the cells and neurons within the ocular microenvironment produce immunomodulating factors that regionally suppress T-cell inflammatory-mediating activities. A biochemical examination of aqueous humor has shown that some of its immunosuppressive activity is associated with alpha-melanocyte stimulating hormone (alpha-MSH). Through alpha-MSH, aqueous humor suppresses IFN-gamma production but promotes proliferation of TGF-beta-producing effector T cells. These effector T cells act as regulatory T cells in that they can suppress immunogenic inflammation mediated by other inflammatory T cells. Moreover, if such regulatory T cells respond specifically to ocular autoantigens, they can suppress the severity and incidence of autoimmune retinitis. The induction of regulatory T cells is a result of alpha-MSH influencing the ability of antigen presenting cells (APC) to activate T cells and directly on T cells responding to presented antigen. It is our plan to characterize the effects of alpha-MSH on the mechanisms of T cell activation. We will also test the possibility that an injection of either alpha-MSH itself or alpha-MSH-induced regulatory T cells can suppress the incidence and severity of ocular autoimmune disease. The results of this project will allow us to understand the molecular and cellular features of immunity within the normal eye. By understanding the activity of intraocular immunomodulatory factors, such as alpha-MSH, it will be possible to induce an immune response that promotes the elimination of pathogens and tumors without the blinding consequences of immunogenic inflammation, that prevents or cures autoimmune diseases of the eye, and that promotes success of corneal, retinal and other tissue transplants.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010752-09
Application #
6819721
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Shen, Grace L
Project Start
1995-04-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
9
Fiscal Year
2005
Total Cost
$325,500
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
Taylor, A W; Dixit, S; Yu, J (2015) Retinal Pigment Epithelial Cell Line Suppression of Phagolysosome Activation. Int J Ophthalmol Eye Sci Suppl 2:1-6
Lee, Darren J; Taylor, Andrew W (2015) Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs. J Leukoc Biol 97:1101-9
Phan, Toan A; Taylor, Andrew W (2013) The neuropeptides ?-MSH and NPY modulate phagocytosis and phagolysosome activation in RAW 264.7 cells. J Neuroimmunol 260:9-16
Lee, Darren J; Taylor, Andrew W (2013) Both MC5r and A2Ar are required for protective regulatory immunity in the spleen of post-experimental autoimmune uveitis in mice. J Immunol 191:4103-11
Taylor, Andrew W (2013) Alpha-melanocyte stimulating hormone (?-MSH) is a post-caspase suppressor of apoptosis in RAW 264.7 macrophages. PLoS One 8:e74488
Taylor, Andrew W (2012) Primary Open-Angle Glaucoma: A Transforming Growth Factor-ýý Pathway-Mediated Disease. Am J Pathol 180:2201-4
Kawanaka, Norikuni; Taylor, Andrew W (2011) Localized retinal neuropeptide regulation of macrophage and microglial cell functionality. J Neuroimmunol 232:17-25
Taylor, Andrew W; Lee, Darren J (2011) The alpha-melanocyte stimulating hormone induces conversion of effector T cells into treg cells. J Transplant 2011:246856
Lee, Darren J; Taylor, Andrew W (2011) Following EAU recovery there is an associated MC5r-dependent APC induction of regulatory immunity in the spleen. Invest Ophthalmol Vis Sci 52:8862-7
Taylor, Andrew W; Kaplan, Henry J (2010) Ocular immune privilege in the year 2010: ocular immune privilege and uveitis. Ocul Immunol Inflamm 18:488-92

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