TRANSPLANTATION TOLERANCE INDUCED BY ANTIGEN PRETREATMENT AND DEPLETING ANTI-CD4 ANTIBODY DEPENDS ON CD4(-CELL REGULATION DURING THE INDUCTION-PHASE OF THE RESPONSE() T)

Adult mice pretreated with donor-specific transfusion and depleting an ti-CD4 antibody 28 days before transplant accept fully allogeneic hear t grafts and become specifically tolerant without further treatment. T he induction of tolerance in this model is not simply a function of CD 4(+) T cell ablation, but appears to depend on residual CD4(+) T cells which escape depletion and engage donor alloantigen during a transien t period of antibody blockade. To test the hypothesis that these CD4() T cells might be responsible for regulating immune responses toward the graft, mice were reconstituted with naive recipient leukocytes at various times after pretreatment. Reconstitution either shortly after pretreatment or shortly after transplant had little effect on graft su rvival. However, when pretreated mice were given an additional dose of depleting anti-CD4 antibody at the time of transplant to target putat ive regulatory cells, naive leukocytes were able to cause acute graft rejection. These data suggest that in clinical transplantation specifi c T cell regulation might develop following pretreatment with antigen and non-depleting anti-CD4 antibodies. Such an approach could provide donor-specific unresponsiveness prior to transplant without the risks associated with sustained CD4(+) T cell depletion.