Is the Malononitrilamide FK778 Better for the Prevention of Acute or Chronic Rejection?

Objective: The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents. Materials and Methods: Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses. Results: In untreated recipients, cardiac allograft survival was 6.2 ± 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 ± 2.8, 18.5 ± 2.7, 25.0 ± 2.5, 20.7 ± 3.8, 14.5 ± 2.2, and 23.2 ± 1.5 days, respectively (P < .05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% ± 16.4%, 44.2% ± 33.6%, 12.3% ± 3.3%, 61.7% ± 18.6%, 18.3% ± 11.3%, 55.0% ± 30.9%, and 8.5% ± 3.5% (P < .05). All 4 high-dose groups showed similar efficacy. Conclusions: When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications.