Analysis of primed donor-specific T cells in recipient mice bearing orthotopic corneal allografts

BACKGROUND: Orthotopic corneal allografts placed in normal eyes of mice are often not rejected, whereas grafts placed in high-risk (neovascularized) eyes are routinely destroyed. Because rejection of solid tissue allografts is usually mediated by donor-specific T cells, we wished to determine the extent to which donor-specific T cells become primed in mice bearing orthotopic corneal allografts in normal and "high-risk" eyes. METHODS AND RESULTS: Our data indicate corneal allografts placed in neovascularized eyes were rejected within 2 weeks, and lymph nodes draining these grafts contained primed donor-specific T cells that proliferated in vitro and displayed cytotoxic activity. By contrast, only 50% of corneal allografts placed in normal eyes experienced rejection. Lymphoid cells from all of these mice displayed donor-specific proliferative activity, irrespective of whether the graft was accepted or rejected. At no time were donor-specific cytotoxic T cells detected. Failure to detect primed cytotoxic T cells was not the result of anergy or deletion of unprimed donor-specific precursors of CTL. CONCLUSIONS: We conclude that primed donor-specific proliferative and cytotoxic T cells directed at MHC alloantigens correlate well with rejection of orthotopic corneal allografts in neovascularized high-risk eyes. However, rejection of cornea allografts in normal eyes does not correlate well with proliferative T cells, nor are donor MHC-specific cytotoxic T cells detected. The possibility is discussed that graft rejection in normal eyes is not mediated by T cells that recognize MHC alloantigens via the direct pathway, but via T cells that recognize donor alloantigens presented by recipient MHC molecules (indirect pathway).