Adenovirus-Mediated PD-L1 Over-Expression Has Differential Effects on Allograft Survival in Murine Islet and Heart Transplant Models.

Program death-1 (PD-1) is a negative regulator of the immune system. Blocking PD-1-mediated negative signaling accelerates autoimmune diseases, while engaging PD-1 with recombinant PD-L1Ig fusion protein potentiates the efficacy of co-stimulation blockade in prolonging allograft survival. However, soluble PD-L1Ig itself showed no graft-protecting effect, in contrast to its strong inhibition of T and B cell activation in vitro when applied in a plate-bound form. In this study, we tested the hypothesis that membrane-bound PD-L1 should prolong allograft survival due to its increased ability to crosslink PD-1 receptor. An adenovirus (Ad.PD-L1) was constructed to encode the full-length mPD-L1, followed by green fluorescent protein (GFP) gene linked by an IRES sequence. A control adenovirus (Ad.Ctrl) was similarly constructed that carries only the GFP gene. In islet transplant model, B6AF1 (H-2b/a) islets were infected with the adenoviruses, and then transplanted into C57BL/6 (H-2b) mice induced diabetic by streptozotocin. In heart transplant model, DBA/2 (H-2d) hearts were perfused with adenoviruses, and then transplanted into C57BL/6 mice. PD-L1 over-expression in islet did not prolong graft survival, but accelerated islet rejection (Ad.PD-L1: 9.0+/−3.5 days; Ad.Ctrl: 13.3+/−2.2 days). In contrast, infection with Ad.PD-L1 prolonged heart allograft survival (15.4+/−5.7 days) in C57BL/6 mice, which promptly rejected DBA/2 hearts (7.0+/−2.3 days, p<0.02). Thus, over-expression of membrane-bound PD-L1 has beneficial effect in an organ/tissue specific manner. Strategies other than direct expression of PD-L1 in the islet b cells need to be devised in order to utilize this negative pathway to prevent rejection.