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JY Niederkorn, S Hegde, E Mayhew; Role of Fas-Induced Apoptosis in the Immune Rejection of Corneal Allografts . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2266.
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Purpose:To determine the mechanisms utilized by CD4+ T cells to mediate corneal graft rejection. Methods:We employed a well-characterized mouse model of penetrating keratoplasty to examine CD4+ T cell effector mechanisms of corneal graft rejection. Corneal allografts were transplanted to CD4 knockout (KO), CD8 KO, perforin KO, FasL deficient, macrophage depleted, and interferon-gamma (IFN-gamma) KO hosts. In vitro studies examined the susceptibility of corneal epithelial and endothelial cells to apoptosis induced by CD4+ T cells and cytokines elaborated by CD4+ T cells (i.e., IFN-gamma and tumor necrosis factor-alpha). Results:100% (10/10) of BALB/c corneal grafts were rejected by wild-type C57BL/6 hosts. By contrast, only 40% of the BALB/c grafts were rejected by C57BL/6 CD4 KO hosts (4/10). Depletion of conjunctival macrophages using liposomes containing clodronate prevented the rejection of BALB/c corneal grafts in C57BL/6 hosts (0/4 rejected), while 87% of grafts in control mice were rejected (7/8). Adoptive transfer of anti-BALB/c CD4+ T cells to C57BL/6 hosts that were depleted of conjunctival macrophages resulted in 100% graft rejection (5/5). CD4+ T cells from C57BL/6 mice immunized with BALB/c alloantigens induced apoptosis of corneal epithelial cells (59%) and endothelial cells (55%). The role of Fas-induced apoptosis by FasL+ CD4+ T cells was examined in vitro and in vivo. While corneal epithelial cells were resistant to Fas-induced apoptosis, corneal endothelial cells were highly susceptible (70% apoptosis). FasL-deficient C57BL/6 mice (gld/gld) displayed a sharp reduction in their capacity to reject BALB/c corneal allografts (37.5% rejection; 9/24) compared to wild-type controls (100% rejection; 8/8). In vitro apoptosis assays indicated that corneal epithelial and endothelial cells were susceptible to apoptosis induced by a CD4+ T cell cytokines, interferon-gamma and TNF-alpha (90% apoptosis of both cell types with each cytokine). In situ TUNEL staining of BALB/c corneal allografts revealed the presence of apoptotic corneal epithelial and endothelial cells on the days preceding corneal graft rejection. Conclusion:CD4+ T cells are necessary for corneal graft rejection and are instrumental in inducing apoptosis of allogeneic corneal cells via Fas, IFN-gamma and tumor necrosis factor-alpha. Strategies that circumvent the apoptotic pathway may have a beneficial effect in preventing corneal graft rejection.
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