Allograft transduction of IL-10 prolongs survival following orthotopic liver transplantation

Interleukin-10 (IL-10) is an ideal candidate cytokine for suppressing the a lloimmune response in transplantation. To determine whether genetic modulat ion of the hepatic graft with IL-IO could prolong survival following orthot opic liver transplantation, we constructed a replication,bn-deficient adeno virus Vector expressing human IL-IO (AdCMVhIL-10). Intraportal injection of this vector into a donor rat 24-48h before grafting resulted in efficient release of IL-IO; into the circulation of a recipient rat after transplanta tion. Moreover, levels of hIL-10 from the suprahepatic vena cava were signi ficantly (1.48-fold) higher than those from the infrahepatic vena cava (P= 0.013), indicating local IL-10 production within the transduced hepatic gra ft. AdCMVhIL-10 induced a prolongation of median survival to more than 87 d ays, with two of five transduced grafts showing more than 100 days of ongoi ng survival, when compared with 11 days for grafts transduced with a contro l adenovirus vector carrying the E, coli p-galactosidase gene (P = 0.0021) and II days for untreated grafts (P = 0.0021). Pathological findings occurr ing in the AdCMVhIL-10-transduced hepatic grafts revealed no evidence of pr ogressive rejection reaction resulting in graft failure. These results demo nstrate that hepatic grafts modulated by IL-10 gene transfer make local and effective immunosuppression feasible in the transplantation setting.