Corneal transplantation is the oldest, most common, and arguably, the most successful form of solid tissue grafting. In the U.S. alone, over 40,000 corneal transplants are performed each year. Even though HLA typing is not performed and topical corticosteroids are the only immunosuppressive agents used, 90% of the corneal transplants will survive the first year. No other form of solid organ transplantation can boast thi success rate under the same conditions. However, in spite of this immune privilege, corneal allografts can fail, with immune rejection being the leading cause of corneal allograft failure. Thus, the long-range goal of this project is to better understand the underlying mechanisms that contribute to immune privilege of corneal allografts and to characterize and hopefully, reverse those conditions that rob the corneal allograft of its immune privilege and lead to allograft rejection. A mouse model of penetrating keratoplasty will be used in prospective studies that address three specific aims pursuant to these long range goals. The first specific aim explores the immune mechanisms whereby allergic diseases such as asthma and allergic conjunctivitis abolish corneal immune privilege and profoundly increase the incidence and tempo of corneal allograft rejection. The second specific aim explores the dramatically different roles of theTh1 cytokine, interferon-y (IFN-y) in different categories of mismatched corneal allografts. In the case of MHC + multiple minor histocompatibility (H)-mismatched grafts, IFN-y is required for graft survival. By contrast, in MHC-matched, minor H mismatched grafts IFN-y promotes corneal allograft rejection. The third specific aim characterizes a recently discovered finding, which demonstrates that corneal surgery jeopardizes the survival of subsequent corneal allografts, even corneal allografts from donors completely unrelated to the donor of the corneal allograft and even more impressively, in corneal allografts placed in the contralateral eye! We have termed this phenomenon "Sympathetic Abrogation of Immune Privilege" (SAIP). SAIP may contribute to the sharp increase in corneal allograft rejection that occurs in patients who receive subsequent corneal allografts from donors unrelated to the donors of the first corneal allograft.

Public Health Relevance

Corneal transplants restore the vision to over 40,000 patients in the U.S. each year. However, immune rejection is the leading cause of corneal transplant failure. This project will identify strategies for reprogramming the immune system so that it tolerates rather than attacks corneal transplants.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007641-26
Application #
8586259
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
1988-08-01
Project End
2016-11-30
Budget Start
2014-01-01
Budget End
2014-11-30
Support Year
26
Fiscal Year
2014
Total Cost
$357,750
Indirect Cost
$132,750
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
Reyes, N J; Chen, P W; Niederkorn, J Y (2013) Allergic conjunctivitis renders CD4(+) T cells resistant to t regulatory cells and exacerbates corneal allograft rejection. Am J Transplant 13:1181-92
Niederkorn, Jerry Y (2013) Corneal transplantation and immune privilege. Int Rev Immunol 32:57-67
Cunnusamy, Khrishen; Chen, Peter W; Niederkorn, Jerry Y (2011) IL-17A-dependent CD4+CD25+ regulatory T cells promote immune privilege of corneal allografts. J Immunol 186:6737-45
Niederkorn, Jerry Y (2011) Cornea: Window to Ocular Immunology. Curr Immunol Rev 7:328-335
Cunnusamy, Khrishen; Paunicka, Kathryn; Reyes, Nancy et al. (2010) Two different regulatory T cell populations that promote corneal allograft survival. Invest Ophthalmol Vis Sci 51:6566-74
Niederkorn, Jerry Y; Larkin, D Frank P (2010) Immune privilege of corneal allografts. Ocul Immunol Inflamm 18:162-71
Niederkorn, Jerry Y; Chen, Peter W; Mellon, Jessamee et al. (2010) Allergic conjunctivitis exacerbates corneal allograft rejection by activating Th1 and th2 alloimmune responses. J Immunol 184:6076-83
Cunnusamy, Khrishen; Chen, Peter W; Niederkorn, Jerry Y (2010) Paradigm shifts in the role of CD4+ T cells in keratoplasty. Discov Med 10:452-61
Cunnusamy, Khrishen; Chen, Peter W; Niederkorn, Jerry Y (2010) IL-17 promotes immune privilege of corneal allografts. J Immunol 185:4651-8
Niederkorn, Jerry Y (2010) High-risk corneal allografts and why they lose their immune privilege. Curr Opin Allergy Clin Immunol 10:493-7

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