Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis

Abstract

IntroductionA major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.MethodsBlood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry.ResultsLymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).ConclusionsIn vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction

“…Previous studies have demonstrated that PD-L1 gene deficiency can protect mice from sepsis-induced organ injury and lethality (11,12) and blockade of PD-1:PD-L1 ligation with antibody prevented the development of colitis in mice (13). Reports have also shown that treatment of immune cells derived from septic patients with PD-L1 antibodies decreased apoptosis and improved their function (14). Additionally, studies have indicated that PD-L1 is not only expressed, but also involved in intestinal mucosal inflammation and regulates gut immune tolerance (15,16).…”

“…Figure 4C Accumulating evidence has demonstrated that the PD-1/PD-L1 pathway plays an important role in regulating the immune-inflammatory response during sepsis, as sepsis can up-regulate PD-L1 expression on a variety of immune cells both in humans (2,14). In the gastrointestinal tract, human gastric epithelial cells express basal levels of PD-L1, and its expression is significantly increased when exposed to Helicobacter Pylori (17).…”

Perioperative Programmed Death 1 Expression on Cd4+ T Cells Predicts the Incidence of Postoperative Infectious Complications

“…Further investigations are necessary to evaluate the mechanism underlying the association between the PD-1-related molecules and postoperative course. The blockade of PD-1 or PD-L1 has been reported to decrease apoptosis and improve cell function in septic patients in vitro (15). In the future, anti-PD-1 or anti-PD-L1 antibodies may represent a useful therapy against perioperative immunosuppressive patients.…”

“…Recently, the role of programmed death 1 (PD-1) has been emphasized (13)(14)(15)(16). Programmed death 1 is a coinhibitory receptor expressed by chronically stimulated CD4 þ T cells and CD8 þ T cells after T-cell activation.…”

The Understanding and Management of Organism Toxicity in Septic Shock

“…Another strategy that has been analyzed is the use of monoclonal antibodies against PD1 and its ligand PDL1. In vitro studies in lymphocytes from septic patients incubated with both antibodies demonstrated improvements in cell function and reductions in apoptosis [66]. A phase Ib/IIa study analyzing the use of PDL1 antibody in patients with sepsis has just been terminated due to “changes in business objectives,” and there are no results available so far (NCT 02576457).…”