Recipient cells expressing single donor MHC locus products can substitute for donor-specific transfusion in the induction of transplantation tolerance when pretreatment is combined with anti-Cd4 monoclonal antibody - Evidence for a vital role of Cd4(+) T cells in the induction of tolerance to class I molecules

Syngeneic cells expressing single donor MHC locus products have been shown to induce specific immunological hyporesponsiveness, but not tolerance, to an allograft. In this study we have attempted to potentiate the beneficial effect of pretreatment with single donor MHC locus products by the addition of anti-Cd4(2) monoclonal antibody to the pretreatment protocol. We show that pretreatment with recipient L cells expressing the products of a single donor locus (K, D, or FA) can induce tolerance to a C57BL/10 (H2(b)) cardiac allograft in C3H/He (H2(k)) mice, when given in combination with the depleting anti-Cd4 monoclonal antibody YTA 3.1.2. Both the induction and maintenance phases of tolerance were found to be antigen-specific. Cells expressing donor class II antigens, IA(b), were found to be most effective. Interestingly, donor class I molecules were also found to be capable of inducing specific unresponsiveness in combination with anti-Cd4, provided an optimal antigenic load was delivered at the time of pretreat ment. Pretreatment with cells expressing donor class I and anti-Cd8 monoclonal antibody had no beneficial effect on graft survival. These data show that single donor MHC locus products can induce immunologic tolerance to fully MHC and minor histocompatibility antigen-mismatched heart grafts when given under the cover of anti-Cd4 mAb. They also show that Cd4(+) T cells play an important role in the induction of specific unresponsiveness to class I alloantigen in vivo and suggest that the blockade of T cells capable of recognizing class I alloantigen presented indirectly is important in the induction of tolerance.