Inhibition of DNA-PK(cs) Prevents Graft Rejection in a Murine Allograft Skin Graft Study

Abstract While the number of patients needing solid organ transplants has steadily increased over the years, the development of safer, more effective transplant drugs has stagnated. Current therapy has been largely successful at thwarting acute cellular rejection; however, antibody-mediated rejection (AMR) remains difficult to treat in the clinic making it the primary cause of graft loss. In this study, we provide proof of principle experiments that DNA-dependent protein kinase catalytic subunit DNA-PK(cs) is a worthwhile target for transplant immunosuppression. In our previous studies, we confirmed that DNA-PK(cs) controls NFAT-induced IL-2 expression, in part, through a mechanism that promotes calcineurin activity by preventing expression of the endogenous calcineurin inhibitor Cabin1. Here, we show that treatment with DNA-PK(cs) inhibitors prevents rejection in a murine skin allograft model by decreasing the production of cytokines including IL2 and IL6 and the infiltration of lymphocytes into the graft. Most importantly, our studies showed that DNA-PK(cs) inhibitors prevented the development of donor-specific antibodies, a driving force behind AMR. These results highlight novel functions for DNA-PK(cs) in the immune system and the potential use of DNA-PK(cs) inhibitors to prevent organ rejection there-bye warranting further investigation.