KINETICS OF INDUCTION OF TRANSPLANTATION TOLERANCE WITH A NONDEPLETING ANTI-CD4 MONOCLONAL-ANTIBODY AND DONOR-SPECIFIC TRANSFUSION BEFORE TRANSPLANTATION - A CRITICAL PERIOD OF TIME IS REQUIRED FOR DEVELOPMENTOF IMMUNOLOGICAL-UNRESPONSIVENESS

The combination of a depleting anti-Cd4(3) monoclonal antibody (mAb) a nd a single donor-specific transfusion before transplantation has been shown to induce operational transplantation tolerance in the majority of cardiac allograft recipients in a mouse model, To examine a protoc ol which might be more clinically relevant, we have modified this tole rance-inducing protocol by substituting the depleting with a nondeplet ing anti-Cd4 mAb, We show that this form of pretreatment can also indu ce immunologic unresponsiveness in most recipients (C3H/He, H2(k)), pr ovided a critical period of time, in this case 28 days, is allowed bet ween pretreatment and transplantation of a fully mismatched heart graf t (H2(b)), When only 1 or 2 weeks were allowed between pretreatment an d transplantation, only slight graft prolongation was obtained when co mpared with recipients receiving anti-Cd4 mAb alone, at these time poi nts, Maintenance of tolerance in this model was due, at least in part, to active mechanisms as immunologic unresponsiveness to donor antigen s could be transferred to naive syngeneic mice by splenocytes from rec ipients bearing long-term functioning grafts, These findings suggest t hat a population of regulatory cells develop after pretreatment with n ondepleting anti-Cd4 mAb and donor-specific transfusion, and that it t akes at least 1 month for these cells to expand and effectively drive the recipient's immune system toward immunologic unresponsiveness.