Whereas many primary, penetrating keratoplasties succeed in humans, an intolerably high proportion fails in """"""""high-risk"""""""" eyes. Immune rejection is the major cause of allograft failure. Our long-term goals are to understand: (a) why primary orthotopic corneal allografts are so well tolerated (display immune privilege), and (b) why grafts in """"""""high-risk"""""""" eyes fare so poorly. During the past 5 years we have made progress toward these goals by demonstrating that: (a) MHC class II and minor H, but not MHC class I, alloantigens are important barriers to corneal allograft acceptance, (b) direct and indirect alloreactive CD4+, but not CD8+, T cells are the dominant mediators of rejection, and (c) comeal endothelium, in part through expression of CD95L, displays inherent immune privilege. Based upon these findings, we have formulated two related hypotheses to guide our experiments: Hypothesis 1. Atypical expression of alloantigens and expression of immunomodulatory molecules on corneal cells contribute to the cornea's immune privileged status. These experiments will determine if expression of alloantigens and/or immunomodulatory molecules on corneal cells, rather than the special qualities of the surrounding graft bed in the eye, contributes to the cornea's status as an immune privileged tissue. Hypothesis 2. MHC class II and/or minor H alloantigen expression rob the corneal epithelium of its graft-acceptance promoting capacity. Our previous data indicated that syngeneic epithelium makes a positive contribution to immune privilege for orthotopic corneal allografts. These experiments will utilize composite comeal grafts composed of recipient epithelium layered over donor stroma/endothelium (and visa versa). We will determine the capacity of composite corneal allografts to induce allosensitization. Our experiments will enable us to discover novel cellular and molecular mechanisms with which to create protocols with greater power to promote graft acceptance in clinical situations where graft failure is all too common.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016486-03
Application #
7221202
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
2005-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$428,227
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
Klocke, Julia; Barcia, Rita N; Heimer, Susan et al. (2011) Spontaneous bacterial keratitis in CD36 knockout mice. Invest Ophthalmol Vis Sci 52:256-63
Gregory, Meredith S; Hackett, Caroline G; Abernathy, Emma F et al. (2011) Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One 6:e17659
Haile, Samuel T; Bosch, Jacobus J; Agu, Nnenna I et al. (2011) Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J Immunol 186:6822-9
Bosch, Jacobus J; Iheagwara, Uzoma K; Reid, Sarah et al. (2010) Uveal melanoma cell-based vaccines express MHC II molecules that traffic via the endocytic and secretory pathways and activate CD8+ cytotoxic, tumor-specific T cells. Cancer Immunol Immunother 59:103-12
Thompson, James A; Srivastava, Minu K; Bosch, Jacobus J et al. (2008) The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes. Cancer Immunol Immunother 57:389-98
Srivastava, Minu K; Bosch, Jacobus J; Thompson, James A et al. (2008) Lung cancer patients'CD4(+) T cells are activated in vitro by MHC II cell-based vaccines despite the presence of myeloid-derived suppressor cells. Cancer Immunol Immunother 57:1493-504
Bosch, Jacobus J; Thompson, James A; Srivastava, Minu K et al. (2007) MHC class II-transduced tumor cells originating in the immune-privileged eye prime and boost CD4(+) T lymphocytes that cross-react with primary and metastatic uveal melanoma cells. Cancer Res 67:4499-506