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

• Published in: Journal of leukocyte biology Vol. 101; no. 2; pp. 543 - 554
• Main Authors: Shindo, Yuichiro, Fuchs, Anja G., Davis, Christopher G., Eitas, Tim, Unsinger, Jacqueline, Burnham, Carey‐Ann D., Green, Jonathan M., Morre, Michel, Bochicchio, Grant V., Hotchkiss, Richard S.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-02-2017; Society for Leukocyte Biology
• Subjects: Animal models; Animals; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cecum; Clinical trials; Cytokines; Cytokines - metabolism; Disease Models, Animal; Effector cells; Host Defense & Pathophysiology; Host-Pathogen Interactions - drug effects; Humans; IFN‐γ; IL‐17; Immunity; Immunity - drug effects; Immunosuppression; Immunotherapy; Infections; innate lymphoid cell; Interferon; Interleukin 17; Interleukin 22; Interleukin 7; Interleukin-7 - pharmacology; Interleukin-7 - therapeutic use; Lung - drug effects; Lung - pathology; Lungs; Lymphocyte Count; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Lymphocytes T; Lymphoid cells; Male; Medical research; Mice; Mice, Inbred C57BL; Morbidity; Mortality; NF-kappa B - metabolism; NF-κB protein; Peritonitis; Pneumonia; Pneumonia - complications; Pneumonia - drug therapy; Pneumonia - immunology; Pneumonia - microbiology; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - physiology; Pseudomonas Infections - complications; Pseudomonas Infections - drug therapy; Pseudomonas Infections - immunology; Pseudomonas Infections - microbiology; Recombinant Proteins - pharmacology; Rodents; Sepsis; Sepsis - complications; Sepsis - pathology; Signal Transduction - drug effects; Signaling; Spleen; Spleen - drug effects; Spleen - pathology; Stat3 protein; STAT3 Transcription Factor - metabolism; Survival; Survival Analysis; TNF‐α; Tumor necrosis factor; γ-Interferon; innate lymphoid cell; immunosuppression; IFN-γ; TNF-α; sepsis; IL-17
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.4A1215-581R

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.