Characterization of cell-mediated immune responses elicited by orthotopic corneal allografts in mice.

PURPOSE Corneal allografts placed orthotopically induce a unique and unusual response in recipient mice. More orthotopic corneal allografts are accepted indefinitely than similar skin allografts. Of the rejected corneal grafts, class I major histocompatibility complex (MHC)-incompatible grafts are rejected less frequently than grafts that express only minor histocompatibility complex (minor H) or MHC plus minor H alloantigens. To describe the spectrum of T cells activated (or not) by orthotpic corneal grafts, the authors examined the development of delayed hypersensitivity (DH) to donor-specific alloantigens. METHODS Recipient BALB/c mice received orthotopic corneal allografts from donor mice that were MHC incompatible at MHC loci only, multiple minor H loci only, or MHC plus multiple minor H loci. These groups of mice were examined to determine when alloantigen-specific DH developed. RESULTS The authors report that all mice, whether they accept or reject grafts, acquire donor-specific DH within 4 weeks of engraftment. This reactivity is primarily directed at minor H, rather than MHC-encoded, alloantigens. Through time, spontaneous DH reactivity disappears in all mice, and thereafter, donor-specific DH can be induced by cognate immunization only in mice that have rejected their cornea grafts. CONCLUSIONS These results can be explained in the context of "direct" and "indirect" pathways of allorecognition. Because normal corneas lack passenger leukocytes, the potential for direct recognition of alloantigens on orthotopic corneal grafts is small. Therefore, T cells activated by orthotopic corneal allografts must recognize donor-derived antigens primarily on recipient antigen presenting cells, that is, through the indirect pathway of allorecognition. Because minor H antigens are the dominant cellular proteins in grafts, it is proposed that minor H determinants are the most immunogenic alloantigens in orthotopic corneal grafts because they are the major source of peptides that will be loaded onto recipient class II molecules for T-cell recognition. We further predict that long-term acceptance of corneal allografts is promoted when recipient mice acquire anterior chamber associated immune deviation (impaired and suppressed DH) directed at minor H alloantigens of the grafts.