title: Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis.
abstract: BACKGROUND
  A 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.
  
  
  METHODS
  Blood 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.
  
  
  RESULTS
  Lymphocytes 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).
  
  
  CONCLUSIONS
  In 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.
authors.forename: Katherine
authors.initials: K
authors.lastname: Chang
authors.forename: Catherine
authors.initials: C
authors.lastname: Svabek
authors.forename: Cristina
authors.initials: C
authors.lastname: Vazquez-Guillamet
authors.forename: Bryan
authors.initials: B
authors.lastname: Sato
authors.forename: David
authors.initials: D
authors.lastname: Rasche
authors.forename: Strother
authors.initials: S
authors.lastname: Wilson
authors.forename: Paul
authors.initials: P
authors.lastname: Robbins
authors.forename: Nancy
authors.initials: N
authors.lastname: Ulbrandt
authors.forename: JoAnn
authors.initials: J
authors.lastname: Suzich
authors.forename: Jonathan
authors.initials: J
authors.lastname: Green
authors.forename: Andriani C
authors.initials: AC
authors.lastname: Patera
authors.forename: Wade
authors.initials: W
authors.lastname: Blair
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Krishnan
authors.forename: Richard
authors.initials: R
authors.lastname: Hotchkiss
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor