THE ENHANCED IMMUNOSUPPRESSIVE EFFICACY OF NEWLY DEVELOPED LIPOSOMAL FK506 IN CANINE LIVER-TRANSPLANTATION

Local delivery of immunosuppressants to the graft and lymphatic tissue is a potential approach to enhance the immunosuppressive efficacy and to alleviate systemic adverse effects simultaneously. By taking advan tage of this method, we developed liposomal FK506. Previous pharmacoki netic study of liposomal FK506 indicated increased FK506 levels in the liver and spleen. Because the liver is the site of the allograft in l iver transplantation and the spleen is a major lymphoid tissue, we hyp othesized that liposomal FK506 would increase immunosuppressive effica cy in liver transplantation. We evaluated this hypothesis in a canine model. Orthotopic liver transplantation was performed using beagle dog s, and the recipients were divided into the following groups: group I, no immunosuppression (n=5); group II, 0.05 mg/kg/day of FK506 i.v. in a commercially available i.v.for 14 days (n=5); and group III, 0.05 m g/kg/day of FK506 i.v. in a liposomal formulation for 14 days (n=5). A ll recipients in group I died within 2 weeks. Recipients in group II d ied within 33 days, In contrast, three recipients in group III survive d for more than 200 days (P<0.05 versus group I or group II). In DNA a nalysis, splenocyte proliferation activity in group III was significan tly suppressed in comparison with group II. These results suggest that liposomal FK506 markedly increase the immunosuppressive efficacy of F K506 in liver transplantation. A local immunosuppressive effect in the grafted liver and significant suppression of splenocyte proliferation might contribute to enhancement of the immunosuppressive efficacy of liposomal FK506.