The long-term goal of this proposed research is to understand the pathogenesis of uveitis, a T cell-mediated autoimmune disease in the eye, using experimental autoimmune uveitis (EAU) as an experimental model. Using in vitro co-culture of uveitigeneic T cells derived from rats with uveitis (EAU) and retinal pigment epithelial (RPE), a major parenchymal cell that might be targeted by uveitogeneic T cells, we have demonstrated that normal RPE cells are capable of inhibiting uveitogeneic T cell functions including proliferation and cytokine production, as evidenced by that T cells are rendered hypo-responsive to their specific antigens presented by APCs when they are pre-exposed to RPE. On the other hand, activated RPE ? is capable of promoting T cell responses by expression of MHC molecules and production of cytokines upon confronting uveitogenic T cells. The reciprocal interaction of uveitogeneic T cell and activated RPE elicit significant amounts of inflammatory mediators such as TNF-a, IFN-r and NO, which may increase target tissue damage. ? The underlying hypothesis of this project is that the outcome of interactions between uveitogenic T cells and the RPE play a critic role in the pathogenesis of the disease. Experiments are designed to determine whether uveitogenic T cells have an increased ability, compared to their nonpathogenic counterparts, to escape the suppression mediated by RPE, or they are more resistant to the apoptotic cell death induced by RPE (Specific Aim 1). We will also test an alternative possibility that uveitogenic T cells are more capable of inducing cascading responses upon interacting with RPEs. Uveitogenic T cells may induce increased expression of MHC class II or co-stimulatory molecules on RPE cells, which in turn, activate the T cells and result in excessive production of inflammatory cytokines and chemokines (Specific Aim 2). The expertise of this laboratory in generating both autoreactive T cells and RPE cells and the availability of various functional tests assessing interaction between T cells and RPE will provide a competitive advantage in the proposed studies. The results of our studies will provide new insights into the pathogenesis of uveitis. ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AED (01))
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Shen, Grace L
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University of Louisville
Schools of Medicine
United States
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Ke, Yan; Jiang, Guomin; Sun, Deming et al. (2011) Anti-CD3 antibody ameliorates experimental autoimmune uveitis by inducing both IL-10 and TGF-? dependent regulatory T cells. Clin Immunol 138:311-20
Ke, Yan; Sun, Deming; Jiang, Guomin et al. (2010) PD-L1(hi) retinal pigment epithelium (RPE) cells elicited by inflammatory cytokines induce regulatory activity in uveitogenic T cells. J Leukoc Biol 88:1241-9
Ke, Yan; Liu, Ke; Huang, Guo-Qiang et al. (2009) Anti-inflammatory role of IL-17 in experimental autoimmune uveitis. J Immunol 182:3183-90
Jiang, Guomin; Ke, Yan; Sun, Deming et al. (2009) A new model of experimental autoimmune keratoconjunctivitis sicca (KCS) induced in Lewis rat by the autoantigen Klk1b22. Invest Ophthalmol Vis Sci 50:2245-54
Ke, Yan; Jiang, Guomin; Sun, Deming et al. (2009) Retinal Astrocytes respond to IL-17 differently than Retinal Pigment Epithelial cells. J Leukoc Biol 86:1377-84
Cui, Yan; Shao, Hui; Lan, Chen et al. (2009) Major role of gamma delta T cells in the generation of IL-17+ uveitogenic T cells. J Immunol 183:560-7
Cui, Yan; Shao, Hui; Sun, Deming et al. (2009) Regulation of interphotoreceptor retinoid-binding protein (IRBP)-specific Th1 and Th17 cells in anterior chamber-associated immune deviation (ACAID). Invest Ophthalmol Vis Sci 50:5811-7
Jiang, Guomin; Ke, Yan; Sun, Deming et al. (2009) Regulatory role of TLR ligands on the activation of autoreactive T cells by retinal astrocytes. Invest Ophthalmol Vis Sci 50:4769-76
Ke, Yan; Jiang, Guomin; Sun, Deming et al. (2008) Ocular regulatory T cells distinguish monophasic from recurrent autoimmune uveitis. Invest Ophthalmol Vis Sci 49:3999-4007
Jiang, Guomin; Ke, Yan; Sun, Deming et al. (2008) Reactivation of uveitogenic T cells by retinal astrocytes derived from experimental autoimmune uveitis-prone B10RIII mice. Invest Ophthalmol Vis Sci 49:282-9

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