SHORT-COURSE SINGLE-AGENT THERAPY WITH AN LFA-3-IGG(1) FUSION PROTEINPROLONGS PRIMATE CARDIAC ALLOGRAFT SURVIVAL

The interaction of T cell costimulatory molecules with their ligands i s required for optimal T cell activation, Interference with such inter actions can induce antigen unresponsiveness and delay xeno- and allogr aft rejection. We have previously shown that LFA3TIP, a soluble human lymphocyte function-associated antigen (LFA)-3 construct, binds CD2 an d inhibits responses of human T cell in vitro. This study reports the first use of a human fusion protein, LFA3TIP, to significantly prolong primate cardiac allograft survival. Based on our observation that LFA 3TIP inhibits baboon allogeneic mixed lymphocyte reactions, we gave ba boon recipients of heterotopic cardiac allografts injections of LFA3TI P, 3 mg/kg i.v., for 12 consecutive days, starting 2 days before trans plantation. This regimen delayed graft rejection fi om an average of 1 0.6+/-2.3 days for human IgG-treated controls (n=5) to an average of 1 8.0+/-5.3 days for LFA3TIP-injected animals (n=7; P less than or equal to 0.01). Grafts from LFA3TIP-treated animals showed markedly diminis hed coronary endothelialitis as compared with control animals. LFA3TIP reached peak serum levels of approximately 100 mu g/ml after 7-9 inje ctions and persisted in the 10-mu g/ml range for 1 to 2 weeks after th e final injection. Despite these blood levels, circulating antibodies to LFA3TIP were not detected in the serum, No renal or hepatic toxicit y was noted. The possible mechanism by which LFA3TIP acts to inhibit g raft rejection is discussed; success in prolonging graft survival when LFA3TIP is used as a single-agent therapy suggests great potential fo r this novel therapeutic agent.