The importance of minor histocompatibility genes in corneal graft rejection was investigated using a model that simulates the major histocompatibility complex (MHC) and minor mismatches of the human allograft more accurately than previous animal models. DA(RT1a) x LEW(RT1(1]F1 hybrid rats were backcrossed to LEW, and the backcross generation were used as corneal graft recipients. Female DA(RT1a) strain animals were used as donors throughout. As in humans, the MHC disparity (a to 1) between each donor-recipient pair could be controlled; minor mismatches were variable and unknown. The MHC haplotype of each backcross individual (either homozygous l/l) or heterozygous a/l) was determined. Depending on this haplotype, the transplanted DA cornea was either matched or mismatched with the recipient for MHC antigens. The average proportion of minor disparate loci was 50%, although this was variable and unknown from recipient to recipient. Some animals of each MHC type were sensitized with three subcutaneous DA strain skin grafts at intervals of 2 weeks. Prior sensitization caused more rapid corneal graft rejection in both MHC mismatched (P less than 0.001) and matched (P less than 0.01) animals. All animals in the two MHC-mismatched groups (sensitized, 26; unsensitized, 17) and most in the MHC-matched groups (sensitized, 25 of 27; unsensitized, all 13) rejected their grafts. The MHC matching resulted in a greater range of survival times, although the difference in survival in unsensitized animals between matched and mismatched groups was not significant (unsensitized, P greater than 0.05; sensitized, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)