Neonatal islets from human PD-L1 transgenic pigs reduce immune cell activation and cellular rejection in humanized nonobese diabetic-scid IL2rγ^null mice

Strong xenorejection limits the clinical application of porcine islet transplantation in type 1 diabetes. Targeting T cell-mediated rejection is one of the main approaches to improve long-term graft survival. Here we study engraftment and survival of porcine islet cells expressing human programmed death-ligand 1 (hPD-L1) in a humanized mouse model.

Neonatal islet-like clusters (NPICCs) from transgenic hPD-L1 (hPD-L1-Tg) and wild-type (Wt) pigs were transplanted into diabetic NOD-scid IL2Rγ^null mice stably reconstituted with human immune cells (hPD-L1 n=10; Wt n=6). Primary endpoint was development of normoglycemia during a 16 weeks observation period after transplantation. Secondary endpoints were porcine C-peptide levels and immune cell infiltration.

Animals transplanted with hPD-L1-Tg NPICCs achieved superior normoglycemic rate (50% versus 0%) and significantly higher plasma C-peptide levels as compared to the Wt group indicating long-term beta cell function. Intracytoplasmic FACS analysis and immunohistochemistry revealed significant decreased frequencies of IFNγ expressing splenic hCD8 positive T cells and reduced intragraft infiltrating immune cells.

We here demonstrate that expression of hPD-L1-Tg provided a strong islet xenograft protection without administration of immunosuppressive drugs. These findings support the hypothesis that hPD-L1 has the capacity to control cellular rejection and therefore represent a very promising transgene candidates for clinical porcine islet xenotransplantation.