Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1

Background Programmed death‐1 (PD‐1) costimulation acts as a negative regulator of T‐cell responses to allografts. However, the role of the PD‐1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T‐cell responses to porcine transfectants overexpressing PD‐Ligand1 (L23‐PD‐L1 cells) are remarkably weak. In this report, we asked whether the PD‐1/PD‐L1 pathway has the potential to diminish xenogeneic immune responses also in vivo. Methods L23‐PD‐L1 or mock transfected control cells (L23‐GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney‐infiltrating rat leukocytes and the induction of anti‐pig antibodies were monitored in grafted animals. Results Assessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23‐PD‐L1 or L23‐GFP control cells. However, the level of MHC class‐II molecules was reduced on macrophages responding to L23‐PD‐L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23‐PD‐L1 cells. In addition, the titers of induced anti‐pig antibodies were significantly lower in rats grafted with L23‐PD‐L1 cells. Conclusions These data suggest that signals triggered by PD‐1–PD‐L1 interaction interfere with activation pathways involved in the induction of cellular and antibody‐mediated immune responses to xenografts in vivo. Targeting of PD‐1 and/or PD‐L1 may be a promising approach for immune modulation after xenotransplantation.