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

Abstract

BackgroundCigarette 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.MethodsKB 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 Ly6CHI monocytes/macrophages and neutrophils. Body weight and clinical scores were recorded throughout the experiment.ResultsWe 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 Ly6CHI monocytes/macrophages and neutrophils.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0577-y) contains supplementary material, which is available to authorized users.

The right microbial stimulus can direct innate immune effector cells to specific organ sites to clear pathology

“…The discovery of tissue-specific microbial memory that can be therapeutically exploited to direct trained innate immune effector cells to sites of pathology has the potential to change the way diseases rooted in immune dysfunction are treated. In addition to treating various cancers and infections, proof-of-principle experiments conducted to date show promise for this approach for the treatment of asthma [32], COPD [33], and inflammatory bowel disease [34]. The clinical application of this immunotherapeutic strategy has been promising thus far, based on Phase 1 and 2 studies in non-small cell lung cancer [8], ulcerative colitis [35], and Crohn’s disease [36].…”

“…QBKPN is a proprietary investigational immunotherapeutic formulated from an inactivated clinical lung isolate of Klebsiella variicola acquired from a patient with pneumonia [8,32,33]. QBECO is a similarly manufactured proprietary investigational immunotherapeutic made from an inactivated clinical isolate of Escherichia coli from a patient with bloody diarrhea.…”

Hypoxia‐inducible factor and bacterial infections in chronic obstructive pulmonary disease

“…NF‐κB is also regulated by PHD (primarily PHD1), which reveals a common molecular pathway connecting hypoxia‐dependent regulation of HIF‐1 and NF‐κB . However, it remains unclear when CS‐induced HIF‐1α activation/overexpression and related pathology become important in the human disease course, which needs further investigation in experimental mouse models that recapitulate human disease features, and confirmed in prospective human studies …”

“…The role of HIF‐1α‐induced PAFR expression as a driver of bacterial infection has not been widely studied in the lungs . Advances in developing representative murine models of human COPD have occurred in the past decade that is enabling us to elucidate the mechanisms involved in HIF‐1α‐induced, PAFR‐mediated bacterial infections in AECOPD …”

“…The role of HIF-1α-induced PAFR expression as a driver of bacterial infection has not been widely studied in the lungs. 63 Advances in developing representative murine models of human COPD have occurred in the past decade 3,[36][37][38][39][40][41]82,85,[133][134][135] that is enabling us to elucidate the mechanisms involved in HIF-1α-induced, PAFR-mediated bacterial infections in AECOPD. 83,[139][140][141] PAFR as a therapeutic target in AECOPD PAFR has been proposed as an antimicrobial therapeutic target for preventing and/or treating COPD exacerbations and pneumococcal pneumonia.…”