The acceptance rate for corneal transplantation, one of the most common types of transplantation performed, is typically between 80- 90%. The reasons for this remarkably high success rate are undoubtedly related to the unique environment of the eye. The eye is one of several organs that manifests properties of immune privilege. Immune privilege is characterized by altered immune responses as is seen in the case of allografts which display prolonged survival when placed into an immune privileged site. While the exact mechanism responsible for immune privilege in the eye is at yet unknown, it has been shown that it probably relies on multiple factors which work together to protect this vital organ from rampant inflammatory processes. These include the production of immunosuppressive cytokines, the localization of neuropeptides in ocular neurons, the strategic placement of specialized antigen presenting cells, and the induction of systemic immune deviation following antigen presentation in the eye. Additionally, it has recently been found that FasL in the eye kills invading Fas+ cells and is a significant protective mechanism for this organ. Furthermore, we have recently reported that virtually all corneas that fail to express functional FasL are rejected by their allogeneic hosts, a compared to a 50% rejection rate for corneas expressing functional FasL. The present application extends our previous observations that Fas ligand (FasL) plays a critical role in murine corneal allograft acceptance to determining whether increasing the functional expression of FasL on the cornea leads to concomitant increase in acceptance of corneal allografts. To that end we will identify those reagents that increase corneal FasL expression and test whether treatment of corneal allografts with such reagents leads to increased cornea allograft acceptance. We will also determine whether FasL expression and function are altered by the immunological state of the cornea. This will be accomplished by monitoring FasL expression in diseased and damaged human corneas and comparing this to that observed in normal human corneas. In parallel, we will stimulate cornea disease in mice and determine whether, over the course of the disease, there are changes in FasL expression from the initial stages of inflammation to the resolution of disease. Finally, preliminary data suggests that neovascularization of the cornea is effected by the presence or absence of functional FasL. Namely, that mice which do not express functional FasL display neovascularization to a greater extent than do mice with normal FasL. Consequently, we propose studies to better define the role that Fas and FasL play in corneal neovascularization.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY012707-02S1
Application #
6414277
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$64,855
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Yin, Xiao-Tang; Tajfirouz, Deena A; Stuart, Patrick M (2014) Murine corneal transplantation: a model to study the most common form of solid organ transplantation. J Vis Exp :e51830
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