Synergy in induction of increased renal allograft survival after portal vein infusion of dendritic cells transduced to express TGF beta and IL-10, along with administration of CHO cells expressing the regulatory molecule OX-2

Dendritic cells (DC), generated from C57BL/6 mouse bone marrow cells cultur ed with GM-CSF and IL-4 for 9 days, were engineered to express constitutive ly the cytokines TGF beta, IL-10, and IL-12, using adenovirus vectors const ructed using an E1-deleted replication-deficient recombinant adenovirus car rying the appropriate cDNA for the relevant cytokines (Ad-TGF beta, Ad-IL-1 2, or Ad-IL-10). C3H mice receiving nontransduced DC or pretransplant infus ion of DC-Ad-LacZ showed increased survival of C57BL/6 renal grafts relativ e to that of control nonimmunized mice. Transfusion of Ad-IL-12-transduced DC abolished this increased survival, leading to a graft survival equivalen t to that of controls with no DC. Optimal graft survival was seen in the gr oup receiving a mixture of DC transduced with constructs for both IL-10 and TGF beta. There was a correlation between increased graft survival and bot h inhibition of the induction of CTL and enhancement of a polarization to p roduce type-2 cytokines (IL-4, IL-10, and TGF beta) on antigen-specific res timulation in vitro. These effects were more pronounced following concomita nt infusion of CRO cells transfected with a full-length cDNA for murine OX- 2. (C) 2000 Academic Press.