EXCEED THE SPACE PROVIDED Tolerance to self or foreign antigens is an active process that is mediated by multiple mechanisms Central tolerance is promoted by negative selection or central deletion of a large number of lymphocytes capable of reacting to self molecules However, some self-reactive lymphocytes remain to be regulated by active tolerance involving regulatory cells, anergy, or apoptosis A breakdown in these mechanisms leads to autoimmune reactivity such as uveitis in the eye The eye is an immune privileged site that has evolved to exhibit immune suppressive mechanisms that prevent immune inflammatory diseases in order to preserve vision Anterior Chamber Associated Immune Deviation (ACAID) is a mouse model allowing for exploration of tolerance inducing mechanisms used by the eye The role of lymphocytes associated with acquired immunity are well described in ACAID literature These studies explore the mechanisms of regulation contributed by innate immune cells in the development of peripheral tolerance induced by antigen inoculation in the anterior chamber (a c ) Building on results from studies in our first funding period we will explore the role of NKT cells in ACAID in sensitized mice, study how the antigen presenting cell (dendritic cell, DC) leads the NKT cell in the process of tolerance development and investigate the role of marginal zone (MZ) B cells in directing NKT ceil function and ACAID We will use cellular immunology methods, immunohistochemistry, molecular biology techniques (including rtPCR and Riboprobe analyses), flow cytometry, confocal microscopy and explore the potential genes involved by performing microgene analyses on genetic differences in 1) subsets of DCs, and 2) NKT cells exposed to tolerogenic APCs, versus MZ B cells The results from these studies wilt generate better understanding of tolerance mechanisms in the eye and the individual as a whole Mechanisms of tolerance induction in the sensitized animals may lead to novel therapies, potentially adaptable to patients with immune inflammatory diseases PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011983-06
Application #
6833964
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Shen, Grace L
Project Start
1999-04-01
Project End
2007-12-31
Budget Start
2005-01-15
Budget End
2005-12-31
Support Year
6
Fiscal Year
2005
Total Cost
$637,521
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
Hsu, S-M; Mathew, R; Taylor, A W et al. (2014) Ex-vivo tolerogenic F4/80? antigen-presenting cells (APC) induce efferent CD8? regulatory T cell-dependent suppression of experimental autoimmune uveitis. Clin Exp Immunol 176:37-48
Lucas, Kenyatta; Karamichos, Dimitris; Mathew, Rose et al. (2012) Retinal laser burn-induced neuropathy leads to substance P-dependent loss of ocular immune privilege. J Immunol 189:1237-42
Qiao, Hong; Lucas, Kenyatta; Stein-Streilein, Joan (2009) Retinal laser burn disrupts immune privilege in the eye. Am J Pathol 174:414-22
Watte, C M; Nakamura, T; Lau, C H et al. (2008) Ly49 C/I-dependent NKT cell-derived IL-10 is required for corneal graft survival and peripheral tolerance. J Leukoc Biol 83:928-35
Sonoda, Koh-Hei; Nakamura, Takahiko; Young, Howard A et al. (2007) NKT cell-derived urokinase-type plasminogen activator promotes peripheral tolerance associated with eye. J Immunol 179:2215-22
Nowak, Michael; Stein-Streilein, Joan (2007) Invariant NKT cells and tolerance. Int Rev Immunol 26:95-119
Sugita, Sunao; Keino, Hiroshi; Futagami, Yuri et al. (2006) B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells. Invest Ophthalmol Vis Sci 47:5376-84
Keino, Hiroshi; Takeuchi, Masaru; Kezuka, Takeshi et al. (2006) Induction of eye-derived tolerance does not depend on naturally occurring CD4+CD25+ T regulatory cells. Invest Ophthalmol Vis Sci 47:1047-55
Keino, Hiroshi; Masli, Sharmila; Sasaki, Shuji et al. (2006) CD8+ T regulatory cells use a novel genetic program that includes CD103 to suppress Th1 immunity in eye-derived tolerance. Invest Ophthalmol Vis Sci 47:1533-42
Zhang-Hoover, Jie; Finn, Patricia; Stein-Streilein, Joan (2005) Modulation of ovalbumin-induced airway inflammation and hyperreactivity by tolerogenic APC. J Immunol 175:7117-24

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