It has been recognized for over a century that the anterior chamber (AC) of the eye is endowed with remarkable properties that permit the long-term survival of histoincompatible tissue and tumor grafts. Ocular immune privilege is the product of multiple, overlapping physiological, anatomical, and immunoregulatory properties of the eye. One of thee mechanisms is the dynamic down-regulation of antigen-specific Th1 and Th2 immune responses and alterations in isotype switching of antibody production. This phenomenon has been termed anterior chamber-associated immune deviation (ACAID) and has been a major focus of the principal investigator's laboratory for the past 25 years. In this application, we propose to characterize another curious form of immune deviation that is revealed when interferon-gamma (IFN-gamma) is not available during the initial immune response to antigens introduced into the AC. This immune deviation is a sharp departure from ACAID. The prototype model for this form of ocular immune deviation is revealed when adenovirus-induced tumor cells (Ad5E1) are introduced into the AC of syngeneic C57BL/6 mice. Intraocular tumors undergo a form of immune rejection that is: a) DTH-independent;b) cytotoxic T lymphocyte (CTL)-independent;c) CD4+ T cell-dependent;and d) interferon-gamma (IFN-gamma)-dependent. By contrast, tumor cells transplanted subcutaneously (SC) undergo immune rejection and prevent the growth of intraocular Ad5E1 tumors in IFN-gamma KO mice, indicating that the protective immune response elicited outside of the eye is IFN-gamma-independent. The SC-induced immunity that prevents intraocular tumor growth is: a) DTH-independent;b) IFN-gamma-independent;c) beta2microglobulin (B2M)-independent;and d) CTL-independent. This project will characterize and analyze this unique form of ocular immune deviation and intraocular tumor immunity. We propose that there are two fundamental pathways for the rejection of immunogenic intraocular tumors, such as Ad5E1. The first pathway is IFN-gamma-dependent and is induced by intraocular tumors. The second pathway is IFN-gamma-independent and CTL-independent, and is induced by extraocular tumors and mediates rejection of intraocular tumors. This project will address three specific aims pursuant to these forms of intraocular tumor rejection: 1) characterize the IFN-gamma-dependent mechanisms of tumor rejection;2) characterize the IFN-gamma-independent mechanisms of tumor rejection;and 3) determine the role of IFN-gamma in the induction of ACAID.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005631-27
Application #
8098013
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1984-12-01
Project End
2013-02-28
Budget Start
2011-07-01
Budget End
2013-02-28
Support Year
27
Fiscal Year
2011
Total Cost
$373,032
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ligocki, Ann J; Niederkorn, Jerry Y (2016) Natural Killer T Cells Contribute to Neutrophil Recruitment and Ocular Tissue Damage in a Model of Intraocular Tumor Rejection. Invest Ophthalmol Vis Sci 57:813-23
Ligocki, Ann J; Niederkorn, Jerry Y (2015) Advances on Non-CD4 + Foxp3+ T Regulatory Cells: CD8+, Type 1, and Double Negative T Regulatory Cells in Organ Transplantation. Transplantation 99:1553-9
Paunicka, Kathryn; Chen, Peter W; Niederkorn, Jerry Y (2012) Role of IFN-? in the establishment of anterior chamber-associated immune deviation (ACAID)-induced CD8+ T regulatory cells. J Leukoc Biol 91:475-83
Coursey, Terry G; Chen, Peter W; Niederkorn, Jerry Y (2012) IFN-?-independent intraocular tumor rejection is mediated by a macrophage-dependent process that leaves the eye intact. J Leukoc Biol 92:939-50
Coursey, Terry G; Chen, Peter W; Niederkorn, Jerry Y (2011) IL-17-dependent, IFN-gamma-independent tumor rejection is mediated by cytotoxic T lymphocytes and occurs at extraocular sites, but is excluded from the eye. J Immunol 187:4219-28
Coursey, Terry G; Chen, Peter W; Niederkorn, Jerry Y (2011) Abrogating TNF-? expression prevents bystander destruction of normal tissues during iNOS-mediated elimination of intraocular tumors. Cancer Res 71:2445-54
Niederkorn, Jerry Y (2011) Cornea: Window to Ocular Immunology. Curr Immunol Rev 7:328-335
Niederkorn, Jerry Y (2009) Immune escape mechanisms of intraocular tumors. Prog Retin Eye Res 28:329-47
Niederkorn, Jerry Y (2009) Role of NKT cells in anterior chamber-associated immune deviation. Expert Rev Clin Immunol 5:137-144
Niederkorn, Jerry Y (2008) Immune regulatory mechanisms in allergic conjunctivitis: insights from mouse models. Curr Opin Allergy Clin Immunol 8:472-6

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