PD-L1-engineered pancreatic islet grafts overcome rejection in allogeneic recipients

Abstract

Abstract The use of chronic immunosuppression is a major hurdle for clinical islet transplantation as a curative modality for the treatment of type 1 diabetes. T effector cells (Teffs) are a main culprit of allograft rejection, and their pathogenic response is kept in check by CD4+CD25+FoxP3+ T regulatory cells (Tregs). The PD-1/PD-L1 immune checkpoint pathway plays an important role in the Teff/Treg balance with demonstrated clinical efficacy in cancer immunotherapy. This study was designed to assess the immunoregulatory function of PD-L1 in preventing allogeneic islet graft rejection. A chimeric protein (SA-PD-L1) containing the extracellular portion of PD-L1 fused to a modified form of core streptavidin was generated. SA-PD-L1 protein was expressed in insect cells and purified. The protein was functional as it enhanced TGF-beta-induced conversion of Teffs into Tregs and suppressed the proliferation of Teffs in response to alloantigens. Importantly, SA-PD-L1 was transiently displayed on the surface of biotinylated islets, and such engineered islets survived for over 100 days in allogeneic recipients treated with a short course (15 days) of low dose rapamycin. In marked contrast, unmodified islets under the same rapamycin regimen were rejected within 20 days. SA-PD-L1-engineered islets without rapamycin, although showing prolonged survival, were eventually rejected within 40 days. These results provide strong proof-of-efficacy and feasibility for the use of SA-PD-L1 protein as an immunomodulator to promote allogeneic islet graft survival in the absence of continued immunosuppression.