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 advantage of this method, we developed liposomal FK506. Previous pharmacokinetic study of liposomal FK506 indicated increased FK506 levels in the liver and spleen. Because the liver is the site of the allograft in liver transplantation and the spleen is a major lymphoid tissue, we hypothesized that liposomal FK506 would increase immunosuppressive efficacy in liver transplantation. We evaluated this hypothesis in a canine model. Orthotopic liver transplantation was performed using beagle dogs, 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 mg/kg/day of FK506 i.v. in a liposomal formulation for 14 days (n=5). All recipients in group I died within 2 weeks. Recipients in group II died within 33 days, In contrast, three recipients in group III survived for more than 200 days (P<0.05 versus group I or group II). In DNA analysis, splenocyte proliferation activity in group III was significantly suppressed in comparison with group II. These results suggest that liposomal FK506 markedly increase the immunosuppressive efficacy of FK506 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.