INDUCTION OF PERSISTENT ALLOGRAFT TOLERANCE IN THE RAT BY COMBINED TREATMENT WITH ANTILEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 AND ANTI-INTERCELLULAR ADHESION MOLECULE-1 MONOCLONAL-ANTIBODIES, DONOR-SPECIFIC TRANSFUSION, AND FK508

We previously reported that a short course of treatment with anti-LFA- 1 and anti-ICAM-1 monoclonal antibodies (mAbs) led to a persistent acc eptance of mouse cardiac allografts, which resulted from the induction of allospecific tolerance. In the present study, we tested the effect of anti-LFA-1 and anti-ICAM-1 mAbs on rat allograft rejection and ana lyzed the mechanisms underlying allograft tolerance, In sharp contrast to the mouse case, a short course of treatment with anti-LFA-1 and an ti-ICAM-1 mAbs led to a persistent acceptance in only half of the trea ted rats when MHC was compatible but mismatched for minor antigens, an d was virtually ineffective when MHC was fully incompatible, However, treatment with these mAbs combined with donor-specific transfusion and FK506 consistently led to a persistent acceptance, even when the MHC was fully incompatible. Donor-specific tolerance was induced by this t reatment, as estimated by skin challenging, In the tolerant rats, prol iferative response and CTL generation against donor-type alloantigen w ere severely impaired but partially restored by exogenous interleukin- 2. Limiting dilution analysis demonstrated that the precursor frequenc y of CTL was decreased in the tolerant rats, as compared with the naiv e rats. These results suggest that donor-reactive T cells were partial ly deleted and rendered anergic in the periphery.