Lentiviral gene transfer of the chemokine antagonist RANTES 9-68 prolongs heart graft survival

Allograft tolerance might be achieved by expressing immunomodulatory proteins through gene therapy. We have evaluated the possibility of promoting significantly allograft survival in a vascularized cardiac allograft model by performing ex vivo gene transfer. We used a lentiviral vector encoding the chemokine antagonist RANTES 9-68 that is capable of competing with native RANTES. The Fisher donor/Lewis recipient rat strain combinations were used and all animals received for the first 5 days posttransplantation a subtherapeutic dose of cyclosporine A (1.5 mg/kg). Ex vivo gene transfer into heart allograft was performed by multiple injections of the SIN.cPPT lentiviral vector, which corresponds to the multiply attenuated, self-inactivating lentivector derived from the human immunodeficiency virus (HIV)-1. About 6% of the cardiac tissue had integrated lentiviral vector, which closely matches the mean in vivo RANTES antagonist expression of 5% obtained by immunohistochemistry. In vivo RANTES 9-68 expression has significantly prolonged graft survival (median [25%-75%]: 20 [17-26] days), compared to the control 15 ([14-15] days; P=0.0007). Furthermore, hearts transduced with RANTES 9-68 showed a significant (P