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Previous studies have shown that the expression of Fas ligand (FasL; CD95L) by donor corneas is critical to their survival when placed on allogeneic recipients. Since there have been reports that the cornea expresses Fas, we tested the idea that FasL on lymphoid cells could be an effector molecule during rejection episodes. When FasL defective BALB/c-gld mice were engrafted with allogeneic corneas, significantly more of these corneas were accepted than by normal BALB/c mice. However, this was not due to impaired FasL-mediated effector function in these mice as the allogeneic corneas did not express detectable Fas by Western blot or RT-PCR analysis. Furthermore, donor corneas without Fas were given no survival advantage, but were rejected similar to wild-type donor allogeneic corneas. Examination of the T cell compartment in gld mice revealed that these cells express higher levels of Fas and are more susceptible to Fas-mediated death than wild-type cells. These results indicate that FasL is not an effector molecule in corneal graft rejection and that gld mice show reduced graft rejection due to greater susceptibility of their T cells to Fas-mediated apoptosis.

Purpose: Neovascularization of the avascular cornea is a significant problem associated with many corneal diseases. Because Fas ligand (FasL) is highly expressed in the cornea, the role of this molecule in controlling corneal neovascularization was examined in this study., Methods: C57BL/6(B6), FasL (CD95L)-deficient B6-gld, and Fas (CD95)-deficient B6-lpr mice were subjected to the suture model of neovascularization. Corneas were evaluated for neovascularization and representative samples subjected to immunohistochemical analysis for expression of Fas antigen and CD31 (platelet-endothelial cell adhesion molecule [PECAM-1]) on vessels that were present in the tissue. Corneas were also explanted and placed in collagen gel cultures to test the ability of anti-Fas antibody to prevent vessel extension from explanted corneas., Results: Immunohistochemical data demonstrated that quiescent vessels express CD31 alone, whereas vessels that penetrate the cornea coexpressed both the Fas antigen and CD31. A significant increase was observed in neovascularization in FasL-deficient B6-gld corneas compared with B6 corneas, and new vessel growth in both B6 and B6-gld was inhibited by anti-Fas antibody. Whereas Fas-deficient B6-lpr corneas displayed significantly less neovascularization than normal B6, B6-lpr mice express Fas on growing vessels. In corneal explant cultures, vessel growth from B6 and lpr mice corneas was inhibited by anti-Fas antibody, confirming functional Fas expression in B6-lpr mice., Conclusions: These data indicate that FasL is an important factor in controlling corneal neovascularization.

Fas (CD95) and Fas ligand (FasL) play major roles in staphylococcal enterotoxin B (SEB)-induced peripheral deletion of Vbeta8+ T cells. We found that peripheral deletion was defective in radiation chimeras with non-functional tissue FasL, regardless of the FasL status of the bone marrow-derived cells. SEB induced a dramatic upregulation of FasL expression and function in nonlymphoid cells of liver and small intestine. This effect was resistant to inhibition by cyclosporin A, which also failed to inhibit peripheral deletion. In SCID animals nonlymphoid tissues did not express FasL in response to SEB unless transplanted lymphocytes were present. Thus, some immune responses induce FasL in nonlymphoid tissues, which in turn kills activated lymphocytes, leading to peripheral T cell deletion.

Although anatomical barriers and soluble mediators have been implicated in immune privilege, it appears that the apoptotic cell death of Fas+ cells by tissue-associated CD95 ligand (Fas ligand, FasL) is an important component. One clinical example of the function of an immune privileged site is the success of human corneal transplants, where a very high percentage of transplants accept without tissue matching or immunosuppressive therapy. Since the mouse cornea expresses abundant Fas ligand and immune privilege has been implicated in the success of these transplants, we examined the role of FasL in corneal transplantation. Our results show that human corneas express functional FasL capable of killing Fas+ lymphoid cells in an in vitro culture system. Using a mouse model for corneal allograft transplantation, FasL+ orthografts were accepted at a rate of 45%, whereas FasL- grafts, or normal grafts transplanted to Fas- mice, were rejected 100% of the time. Histological analysis found that FasL+ grafts contained apoptotic mononuclear cells indicating the induction of apoptosis by the graft, while rejecting FasL- corneas contained numerous inflammatory cells without associated apoptosis. Taken together our results demonstrate that FasL expression on the cornea is a major factor in corneal allograft survival and, thus, we provide an explanation for one of the most successful tissue transplants performed in humans.