Tolerance to self and 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 escape this process and remain present in the adult and must be regulated by active tolerance mechanisms that involve T regulatory cells, anergy, or apoptosis. Here, we will study a model for peripheral tolerance that can be induced through the eye called Anterior Chamber Associated Immune Deviation (ACAID). The eye is an immune privileged site that has evolved to exhibit immunosuppressive mechanisms that prevent immune inflammatory reactions in the eye in order to preserve vision. In order to better understand how we might adapt ACAID mechanism to immunotherapy of autoimmune disease in the eye, our first aim will investigate the mechanisms of ACAID induction in sensitized vs na?ve mice. During these studies we will also induce antigen specific ACAID in mice that receive cornea transplants or in which experimental autoimmune uveitis is induced by transferring in vitro generated ACAID- like tolerogenic APC, and explore the role of the NKT cell in this therapy. The results of these studies will raise the possibility of a cell based therapy to treat immune inflammatory diseases in the eye.

Public Health Relevance

The study of innate immune cells in immune deviation initiated through immune privilege sites is a novel and useful area for research. It is known that the innate immune NKT cell is involved in self-tolerance since in its absence, a variety of autoimmune diseases arise. Furthermore, the study of eye induced tolerance in sensitized mice and the dependence on NKT cells is novel and not well studied. The study of the generation of peripheral tolerance to antigens to which the host is already sensitized is directly related to the development of the novel therapies for treatment of immune inflammatory disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY011983-09A2
Application #
7655143
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Shen, Grace L
Project Start
1999-04-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
9
Fiscal Year
2009
Total Cost
$610,866
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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