Immune privilege is maintained in the eye by multiple cellular mechanisms that prevent damaging inflammatory immune responses against pathogens or self-antigens in the eye. These cellular mechanisms include production of immunosuppressive cytokines and neuropeptides in the ocular environment such as transforming growth factor-beta, and alpha-melanocyte stimulating hormone, low MHC expression, lack of lymphatic drainage, a blood-ocular barrier, Fas Ligand expression, and anterior chamber associated immune deviation. We have successfully identified a molecular mechanism that may play a role in maintaining ocular immune privilege and provides a gene-based explanation for the exceptionally high success rate of corneal transplants in low risk patients without donor-typing and matching. Based on strong evidence that DNA methylation occurs in tumor cells when they are introduced into the eye, the hypothesis of my research is that the ocular environment induces epigenetic methylation that downregulates gene expression in foreign tissues within the eye and mitigates destructive inflammatory ocular immune responses. Our research addresses: (i) Identifcation of methyltransferases upregulated by ocular environment responsible for gene methylation, using microarray analysis, real-time PCR, and Western blot analysis, ii) Determining whether methylation initiated by the ocular environment regulates gene expression by specifically methylating individual genes or by inducing global methylation and chromatin remodeling, using promoter-reporter vector assays, methylation specific PCR and chromatin immunoprecipitation techniques, and (iii) Isolation and identification of the factor(s)in the ocular environment responsible for triggering epigenetic gene regulation, using protein fractionation, mass spectroscopy, and proteome analysis. A better understanding of how the eye utilizes the molecular mechanisms of epigenetic regulation to maintain ocular immune privilege and prevent destructive innate and adaptive immune responses that threaten the survival of transplanted corneal tissue will provide the basis for development of new gene regulation-based strategies to improve chances of successful corneal transplants in high-risk patients whose prognosis for accepting a transplant are extremely poor due to persistent corneal inflammation.
RESEARCH INTERESTS
Epigenetic Gene Regulation
Immune Privilege and Immunoregulation
Ocular Tumors
Corneal Transplantation
RECENT PUBLICATIONS
Dace DS, Chen PW, Alizadeh H, Niederkorn JY., "Ocular immune privilege is circumvented by CD4+ T cells, leading to the rejection of intraocular tumors in an IFN-g dependent manner." J Leukocyte Biol., 81:421?429, February 2007
Dru S. Dace, Peter W. Chen, and Jerry Y. Niederkorn, "CD8+ T Cells Circumvent Immune Privilege in the Eye and Mediate Intraocular Tumor Rejection by a TNF-{alpha}-Dependent Mechanism" Journal of Immunology, 178::6115-6122, May 2007
Dace DS, Chen PW, Niederkorn, JY, "CD4+ T cell dependent tumor rejection in an immune privileged environment requires macrophages." Immunology, 123:367-377, 2008
Yang W, Chen PW, Li H, Alizadeh H, and Niederkorn JY, "PD-L1: PD-1 Interaction Contributes to the Functional Suppression of T-Cell Responses to Human Uveal Melanoma Cells In Vitro." Invest. Ophthal. Vis. Sci., 49:2518-2525, 2008
Niederkorn, JY, Chen PW, Stevens CN, Mellon JK, Mayhew E, "Allergic airway hyper-reactivity increases the risk for corneal allograft rejection." Amer. J. Transplantation, 9:1017-1026, September 2009
SIGNIFICANT PUBLICATIONS
Chen PW, Uno T, Ksander BR., "Tumor Escape Mutants Develop Within an Immune Privileged Environment in the Absence of T Cell Selection." J. Immunol., 177:162-168, July 2006
Chen PW, Murray TG, Uno T, Salgaller ML, Reddy R., Ksander BR., "Expression of MAGE genes in ocular melanoma from primary to metastatic disease." Clin. Exp. Metastasis, 15:509-518, 1997
Chen PW., Ksander BR., "Influence of immune surveillance and immune privilege on formation of intraocular tumors" Chemical Immunology and Allergy, Vol. 92:276 - 289, January 2007
Chen PW, Ksander BR., "Termination of Systemic Immunity in the Presence of Intraocular Tumors: Influence of Ocular Immune Privilege on Tumor Vaccines." Cur. Eye Res., 31:43-55, January 2006
Chen PW, Mellon JK, Mayhew E, Wang, S, He Y, Hogan, N, and Niederkorn, JY, "Uveal melanoma expression of indoleamine 2, 3 deoxygenase: Establishment of an immune privileged environment by tryptophan depletion" Experimental Eye Research, 85:617-625, 2007
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