PD-L1 Deficiency within Islets Reduces Allograft Survival in Mice

Abstract

BackgroundIslet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time.MethodsGlucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients.ResultsPD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity.ConclusionsThis is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses.

Pigs expressing the human inhibitory ligand PD‐L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties

“…With regard to transplantation immunology and biology, PD‐L1 expression in the graft has been discussed to be counter‐regulator of rejection in liver and kidney transplants . This is in line with the observation that survival of islet cell allografts was reduced in the absence of PD‐L1 . In addition to its capacity to decrease the intensity of anti‐graft responses, the PD‐1/PD‐L1 system has also been described to be involved in the acquisition of transplant tolerance .…”

“…19 This is in line with the observation that survival of islet cell allografts was reduced in the absence of PD-L1. 20 In addition to its capacity to decrease the intensity of anti-graft responses, 21 the PD-1/PD-L1 system has also been described to be involved in the acquisition of transplant tolerance. 22,23 The two known ligands of PD-1 (PD-L1 and PD-L2) may differently be involved in the regulation of alloreactivity in CD4 + and CD8 + T-cell subsets.…”

Human regulatory macrophages are potent in suppression of the xenoimmune response via indoleamine‐2,3‐dioxygenase‐involved mechanism(s)

“…PD‐L1 is expressed by many types of cells including various immune cells such as macrophages, and it also plays a central role in down‐regulating activated T cells by suppressing their proliferation and cytokine secretion in the periphery . Studies using transplant animal models have shown that upregulated PD‐L1 expression is required or important for the maintenance of cardiac allograft tolerance and to prolong skin graft survival in mice, and that PD‐L1 deficiency within islets accelerates islet allograft rejection . Given our finding of a dramatically upregulated PD‐L expression on Mreg, we would suggest that PD‐L may act as another mediator for Mreg to suppress the xenogeneic response, although its precise role in Mreg‐mediated regulation in the xenogeneic response remains to be investigated.…”

Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression

“…SA-PDL1-engineered islets survive indefinitely in allogeneic hosts under a short course of rapamycin regimen Pancreatic islets from mice genetically modified to lack PD-L1 were shown to undergo accelerated rejection in allogeneic recipients, emphasizing the importance of this immune checkpoint ligand in modulating alloreactive responses (33). Thus, we assessed the impact of SA-PDL1 protein displayed on the surface of islet grafts on survival in allogeneic hosts (Fig.…”