Immunization of Lewis rats with myelin basic protein (MBP) and its peptides induces autoimmune encephalomyelitis (EAE) as well as an anterior uveitis (AU) that closely mimics human anterior uveitis. This reflects the observation in humans that a significant percentage (20%) of multiple sclerosis patients suffer from AU. This proposal stems from the observation that MBP-induced eye disease was more persistent than the disease of the CNS and the uveitogenic activity of MBP-reactive T cells does not always parallel with the encephalitogenic activity of the cell, indicating that the mechanism involved in the pathogenesis and tolerance induction of the two diseases differ. These proposed studies will exploit a large volume of data and T cell lines obtained in my laboratory during the previous study of EAE and MBP to characterize uveitogenic T cells, and to elucidate the pathogenic mechanism by which MBP-induces different autoimmune diseases in the CNS and in the eye. We propose to determine whether uveitogenic and encephalitogenic T cells are distinct or overlapping subset(s) of MBP-specific T cells and to determine whether uveitogenic T cells have augmented activation in the eye leading to prolonged disease expression. Finally, we will determine whether the regulatory T cells elicited by MBP-specific encephalitogenic T subsets are less effective in neutralizing uveitogenic T cell activity and whether non-specific inhibitory cells like NKT cells will be more effective in down-regulating diverse uveitogenic T cells. Our proposal will be greatly promoted by the MBP-specific T cells lines already available in my laboratory and the experience of isolation and characterization of autoimmune regulatory T cells and autoreactive T cells elicited by whole MBP antigen and altered peptides. This project will enhance our ability to understand the mechanisms for the development of autoimmune diseases and also identify targets for the therapeutics in uveitis.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014366-04
Application #
7084506
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Shen, Grace L
Project Start
2003-08-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$287,091
Indirect Cost
Name
University of Louisville
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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
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
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
Song, Lei; Le, Junyi; Ye, Fei et al. (2008) Sequence 168 to 177 of interphotoreceptor retinoid-binding protein (IRBP) is an antigenic epitope for autoreactive CD8 T cells in the B10RIII mouse. J Neuroimmunol 193:68-76
Cheng, Lan; Cui, Yan; Shao, Hui et al. (2008) Mouse gammadelta T cells are capable of expressing MHC class II molecules, and of functioning as antigen-presenting cells. J Neuroimmunol 203:3-11
Hao, Siguo; Liu, Yongqing; Yuan, Jinying et al. (2007) Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses. J Immunol 179:2731-40
Peng, Yong; Han, Gencheng; Shao, Hui et al. (2007) Characterization of IL-17+ interphotoreceptor retinoid-binding protein-specific T cells in experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 48:4153-61
Peng, Yong; Shao, Hui; Ke, Yan et al. (2007) Minimally activated CD8 autoreactive T cells specific for IRBP express a high level of Foxp3 and are functionally suppressive. Invest Ophthalmol Vis Sci 48:2178-84

Showing the most recent 10 out of 25 publications