CTLA4IgG treatment induces long-term acceptance of rat small bowel allografts

Background. CTLA4 immunoglobulin (Ig)G that binds to B7 effectively inhibit s the signaling of CD28/CTLA4-B7 pathway and induces antigen specific T cel l unresponsiveness in vitro and in vivo. Using CTLA4IgG, we examined induct ion of long-term graft survival and the mechanism of maintenance of toleran ce in rat allogeneic small bowel transplantation. Methods. Small bowels of Brown-Norway rats (RT1(n)) were heterotopically tr ansplanted into Lewis rats (RT1(l)). Recipients were treated with an i.p. i njection of either CTLA4IgG or control IgG for 7 days. Results. kong-term survival was observed in rats treated with CTLA4IgG, whe reas control rats died within 16 days after transplantation. To examine whe ther a tolerant state was established in long-term survival rats, secondary transplantation was performed using small bowels of Brown-Norway rats or A CI (RT1(b)) rats. It was demonstrated that small bowels of Brown-Norway rat s were accepted; however, those of ACI rats were rejected within 10 days. S erum concentrations of interleukin (IL)-4 were maintained at >50 mu g/ml fo r 7 days after transplantation in rats treated with CTLA4IgG but <15 mu g/m l in control rats. IL-2 concentration was reduced to half in CTLA4IgG-treat ed rats compared with that in control recipients. Serum IFN-gamma in CTLA4I gG-treated recipients increased after transplantation and was not distingui shable from that of control recipients during the first 7 days after transp lantation. Conclusion. We demonstrated that CTLA4IgG treatment alone for 7 days induce d a long-term donor specific tolerance in rat allogeneic small bowel transp lantation. The induction of long-term acceptance of small bowel allografts by CTLA4IgG is not caused by simply the shift of anti-alloimmune responses from Th1 to Th2 cytokine production.