LONG-TERM ACCEPTANCE OF MAJOR HISTOCOMPATIBILITY COMPLEX-MISMATCHED CARDIAC ALLOGRAFT INDUCED BY A LOW-DOSE OF CTLA4IGM PLUS FK506

The immunosuppressant FK506 prolongs allograft survival. However, at t herapeutic doses it has significant side effects. A fusion protein con sisting of the extracellular portion of CTLA4 and the Fe portion of hu man IgG (CTLA4IgG) also prolongs allograft survival, but large doses o f CTLA4IgG are required for the induction of cardiac allograft accepta nce. Therefore, we constructed a pentameric form of a new CTLA4 fusion protein, CTLA4IgM. We tested whether low doses of CTLA4IgG or CTLA4Ig M in combination with subtherapeutic doses of FK506 can prolong allogr aft survival in a synergistic fashion. C57BL/6 (H-2(b)) neonatal heart s were transplanted to CBA/J (H-2(k)) mice in a heterotopic, nonvascul arized cardiac allograft model. The findings demonstrate that a combin ation of low doses of FK506 plus a pentameric form of CTLA4Ig, CTLA4Ig M, leads to significant graft survival, while a combination of FK506 p lus CTLA4IgG does not.