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J Leukoc Biol. 2017 Feb;101(2):543-554. doi: 10.1189/jlb.4A1215-581R. Epub 2016 Sep 14.

Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia.

Author information

1
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA; yshindo@med.nagoya-u.ac.jp.
2
Institute for Advanced Research, Nagoya University, Nagoya, Japan.
3
Acute and Critical Care Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
4
Host Defense DPU, Infectious Diseases TAU, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
5
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.
6
Pathology and Immunology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
7
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
8
Revimmune, Inc., Bethesda, Maryland, USA, and.
9
Anesthesiology, Medicine, Surgery, and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.

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.

KEYWORDS:

IFN-γ; IL-17; TNF-α; immunosuppression; innate lymphoid cell; sepsis

PMID:
27630218
PMCID:
PMC5235902
DOI:
10.1189/jlb.4A1215-581R
[Indexed for MEDLINE]
Free PMC Article

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