Journal Article

Attenuating immune pathology using a microbial-based intervention in a mouse model of cigarette smoke-induced lung inflammation

Bazett, Mark, Biala, Agnieszka, Hansbro, Philip M., Gunn, Hal, Zeglinksi, Matthew R., Bosiljcic, Momir, Kalyan, Shirin, Huff, Ryan D., Hirota, Jeremy A.

2017

Overview

Background Cigarette smoke exposure is the major risk factor for developing COPD. Presently, available COPD treatments focus on suppressing inflammation and providing bronchodilation. However, these options have varying efficacy in controlling symptoms and do not reverse or limit the progression of COPD. Treatments strategies using bacterial-derived products have shown promise in diseases characterized by inflammation and immune dysfunction. This study investigated for the first time whether a novel immunotherapy produced from inactivated Klebsiella (hereafter referred to as KB) containing all the major Klebsiella macromolecules, could attenuate cigarette smoke exposure-induced immune responses. We hypothesized that KB, by re-directing damaging immune responses, would attenuate cigarette smoke-induced lung inflammation and bronchoalveolar (BAL) cytokine and chemokine production. Methods KB was administered via a subcutaneous injection prophylactically before initiating a 3-week acute nose-only cigarette smoke exposure protocol. Control mice received placebo injection and room air. Total BAL and differential cell numbers were enumerated. BAL and serum were analysed for 31 cytokines, chemokines, and growth factors. Lung tissue and blood were analysed for Ly6C HI monocytes/macrophages and neutrophils. Body weight and clinical scores were recorded throughout the experiment. Results We demonstrate that KB treatment attenuated cigarette smoke-induced lung inflammation as shown by reductions in levels of BAL IFNγ, CXCL9, CXCL10, CCL5, IL-6, G-CSF, and IL-17. KB additionally attenuated the quantity of BAL lymphocytes and macrophages. In parallel to the attenuation of lung inflammation, KB induced a systemic immune activation with increases in Ly6C HI monocytes/macrophages and neutrophils. Conclusions This is the first demonstration that subcutaneous administration of a microbial-based immunotherapy can attenuate cigarette smoke-induced lung inflammation, and modulate BAL lymphocyte and macrophage levels, while inducing a systemic immune activation and mobilization. These data provide a foundation for future studies exploring how KB may be used to either reverse or prevent progression of established emphysema and small airways disease associated with chronic cigarette smoke exposure. The data suggest the intriguing possibility that KB, which stimulates rather than suppresses systemic immune responses, might be a novel means by which the course of COPD pathogenesis may be altered.

• Publisher: BioMed Central,Nature Publishing Group,BMC
• Subject: Allergies / Alveoli / Animals / Asthma / Attenuation / Blood / Body weight / Bronchodilation / Bronchodilators / Bronchus / Cell activation / Chemokines / Chronic obstructive pulmonary disease / Cigarette smoke / Cigarette Smoking - adverse effects / Cigarettes / Colleges & universities / Colony-stimulating factor / COPD / CXCL10 protein / Cytokines / Cytokines - immunology / Disease Models, Animal / Emphysema / Exposure / Female / Granulocyte colony-stimulating factor / Growth factors / Immune response / Immunomodulators / Immunotherapy / Immunotherapy - methods / Inflammation / Inflammation Mediators - immunology / Inflammatory bowel disease / Injection / Interleukin 17 / Interleukin 6 / Klebsiella / Klebsiella - immunology / Leukocytes (neutrophilic) / Lungs / Lymphocytes / Macromolecules / Macrophages / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Microorganisms / Monocytes / mucosal immunology / Neutrophils / Pathogenesis / Pathology / Pneumology/Respiratory System / Pneumonia - etiology / Pneumonia - immunology / Pneumonia - therapy / Risk factors / Smoke / Software / Streptococcus infections / Tobacco smoke / Treatment Outcome / Vaccines, Inactivated - administration & dosage / γ-Interferon