title: Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia.
abstract: Patients with protracted sepsis develop impaired immunity, which predisposes them to acquiring secondary infections. One of the most common and lethal secondary infections is Pseudomonas aeruginosa pneumonia. Immunoadjuvant therapy is a promising approach to reverse sepsis-induced immunosuppression and improve morbidity and mortality from secondary infections. Interleukin-7 is an immunoadjuvant that improves survival in clinically relevant animal models of polymicrobial peritonitis and in fungal sepsis. This study investigated the effect of recombinant human interleukin-7 (rhIL-7) on survival in a 2-hit model of sublethal cecal ligation and puncture followed by P. aeruginosa pneumonia. Potential immunologic mechanisms responsible for the rhIL-7 putative beneficial effect were also examined, focusing on IL-17, IL-22, IFN-γ, and TNF-α, cytokines that are critical in the control of sepsis and pulmonary Pseudomonas infections. Results showed that rhIL-7 was highly effective in preventing P. aeruginosa-induced death, i.e., 92% survival in rhIL-7-treated mice versus 56% survival in control mice. rhIL-7 increased absolute numbers of immune effector cells in lung and spleen and ameliorated the sepsis-induced loss of lung innate lymphoid cells (ILCs). rhIL-7 also significantly increased IL-17-, IFN-γ-, and TNF-α-producing lung ILCs and CD8 T cells as well as IFN-γ- and TNF-α-producing splenic T cell subsets and ILCs. Furthermore, rhIL-7 enhanced NF-κB and STAT3 signaling in lungs during sepsis and pneumonia. Given the high mortality associated with secondary P. aeruginosa pneumonia, the ability of rhIL-7 to improve immunity and increase survival in multiple animal models of sepsis, and the remarkable safety profile of rhIL-7, clinical trials with rhIL-7 should be considered.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA; yshindo@med.nagoya-u.ac.jp.|Institute for Advanced Research, Nagoya University, Nagoya, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shindo
authors.affiliation: Acute and Critical Care Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Anja G
authors.initials: AG
authors.lastname: Fuchs
authors.affiliation: Acute and Critical Care Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Davis
authors.affiliation: Host Defense DPU, Infectious Diseases TAU, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Eitas
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Unsinger
authors.affiliation: Pathology and Immunology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Carey-Ann D
authors.initials: CD
authors.lastname: Burnham
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Green
authors.affiliation: Revimmune, Inc., Bethesda, Maryland, USA, and.
authors.forename: Michel
authors.initials: M
authors.lastname: Morre
authors.affiliation: Acute and Critical Care Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Grant V
authors.initials: GV
authors.lastname: Bochicchio
authors.affiliation: Anesthesiology, Medicine, Surgery, and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007167:Immunotherapy; D015851:Interleukin-7 / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D015851:Interleukin-7; D016328:NF-kappa B; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor
keywords: IFN-γ; IL-17; TNF-α; immunosuppression; innate lymphoid cell; sepsis