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

Abstract

Dendritic cells (DC), generated from C57BL/6 mouse bone marrow cells cultured with GM-CSF and IL-4 for 9 days, were engineered to express constitutively the cytokines TGFbeta, IL-10, and IL-12, using adenovirus vectors constructed using an E1-deleted replication-deficient recombinant adenovirus carrying the appropriate cDNA for the relevant cytokines (Ad-TGFbeta, Ad-IL-12, or Ad-IL-10). C3H mice receiving nontransduced DC or pretransplant infusion of DC-Ad-LacZ showed increased survival of C57BL/6 renal grafts relative to that of control nonimmunized mice. Transfusion of Ad-IL-12-transduced DC abolished this increased survival, leading to a graft survival equivalent to that of controls with no DC. Optimal graft survival was seen in the group receiving a mixture of DC transduced with constructs for both IL-10 and TGFbeta. There was a correlation between increased graft survival and both inhibition of the induction of CTL and enhancement of a polarization to produce type-2 cytokines (IL-4, IL-10, and TGFbeta) on antigen-specific restimulation in vitro. These effects were more pronounced following concomitant infusion of CHO cells transfected with a full-length cDNA for murine OX-2.