Induction of persistent allograft tolerance in the rat by combined treatment with anti-leukocyte 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 acceptance 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 analyzed the mechanisms underlying allograft tolerance, In sharp contrast to the mouse case, a short course of treatment with anti-LFA-1 and anti-ICAM-1 mAbs led to a persistent acceptance in only half of the treated rats when MHC was compatible but mismatched for minor antigens, and 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 treatment, as estimated by skin challenging, In the tolerant rats, proliferative response and CTL generation against donor-type alloantigen were severely impaired but partially restored by exogenous interleukin-2. Limiting dilution analysis demonstrated that the precursor frequency of CTL was decreased in the tolerant rats, as compared with the naive rats. These results suggest that donor-reactive T cells were partially deleted and rendered anergic in the periphery.