Review
Immunoregulatory and immunostimulatory responses of bacterial lysates in respiratory infections and asthma

https://doi.org/10.1016/j.anai.2015.02.008Get rights and content

Abstract

Objective

This review focuses on the current understanding of the molecular mechanisms of bacterial lysates, evidence of an induction of innate immunity, and the interaction with immunoregulators, dendritic cells, and regulatory T cells. Clinical relevance is summarized based on the observed mechanisms of action of bacterial lysates.

Data Sources

Academic Search Complete, CENTRAL, Health Source: Nursing/Academic Edition, MEDLINE, and Cochrane databases.

Study Selections

Three independent researchers focused on primary and secondary end points in systematic reviews, meta-analyses, and randomized controlled trials using bacterial lysates as a verum group or within a subpopulation of larger studies. Interventional and observational studies on novel applications also were included. Preclinical studies included murine models focusing on toll-like receptors (TLRs) and regulatory T cells and on the relation with asthma and respiratory immunity.

Results

Bacterial lysates have been observed to induce synergistic TLR-2/6- and TLR-9–dependent innate immunity. It has positive outcomes in decreasing recurrent respiratory tract infections in childhood and adult chronic obstructive pulmonary disease. This class of immunostimulants shows some evidence of mitigating infection morbidity in children and decreasing the frequency of inflammatory episodes (ie, wheezing exacerbations) in children with asthma. Preclinical studies suggest that regulatory T cells can be induced by bacterial lysates and might attenuate T-helper cell type 2 allergic responses.

Conclusion

Although successful prevention against all common respiratory pathogens is not possible, bacterial lysates seem capable of targeting specific immunocompetent cells through pathogen recognition receptor activation. Current challenges include clarifying the duality of immunoregulatory and immunostimulatory responses in children at risk for allergy. Larger clinical trials are required to elicit efficacy in allergy prevention.

Introduction

In light of the increasing prevalence of non-communicable diseases, the “hygiene hypothesis” postulated by Strachan1 pointed out the evolutionary necessity of contact between the host and environment. Pioneering works by several groups have since provided support for the relation between living in cleaner environments and the development of allergic sensitization and asthma.[2], [3], [4] These groups also hypothesized that infancy—when immune system development takes place—is a crucial period during which allergic phenotypes surface, and that increasing exposure to microbial antigens during this period can lower the risk of atopy.4 It has been found that the ingestion of probiotic bacteria during pregnancy and continued probiotic consumption during the postnatal period by the infant can decrease the risk of developing atopic dermatitis and food hypersensitivity at older ages.5

Although the ingestion of viable commensal bacteria can affect the development of allergic airway diseases, there is evidence to suggest that bacteria-derived cellular extracts (ie, bacterial lysates) can stimulate and modulate lung immunity through local and systemic pathways.[6], [7] Bacterial lysates have been used to decrease recurrent respiratory tract infections in otherwise healthy children and in adults with chronic obstructive pulmonary disease (COPD), and their oral ingestion has been shown to decrease the number of virus-induced wheezing episodes in children with asthma.8 Remarkably, these preparations also have preventative effects on food sensitization and eczema in children.[9], [10] This review highlights the current understanding of how bacterial lysates modify immune responses and discusses their effectiveness in enhancing immunity in the respiratory tract.

Section snippets

Bacterial Lysate Composition and Locoregional Effects

Bacterial lysates exist as mechanically fractioned particulates or chemically degraded lyophilized cells derived from pathogenic bacterial strains responsible for respiratory tract infections. OM-85 BV (also known as Broncho-Vaxom, Broncho-Munal, Ommunal, Paxoral, and Vaxoral) is the most frequently cited of these compounds and contains extracts derived from 8 bacterial species (Staphylococcus aureus, Streptococcus viridans, Streptococcus pyogenes, Diplococcus pneumoniae, Klebsiella pneumoniae,

Interaction of Bacterial Lysates with Pattern Recognition Receptors

The protective role of specific or polyclonal IgA does not explain the protection achieved in experimental animals treated with bacterial antigens and then challenged with completely different pathogens. For example, rodents treated with H influenzae–derived bacterial lysates showed an enhanced immune response to challenges by influenza A,[11], [28] Streptococcus pneumoniae,29 and Aspergillus fumigatus.30 In mice infected with H1N1 influenza virus and Salmonella typhimurium, bacterial lysates

Clinical Outcomes of Bacterial Lysate Therapy in Childhood Respiratory Diseases

Persistent lung tissue inflammation during childhood can affect lung maturation and predispose to chronic airway disease.40 Acute respiratory tract infections account for a large percentage of pediatric illnesses, many of which are self-limiting viral infections that do not require additional follow-up. The incidence of these infections can be very high; it is estimated that up to 25% of children younger than 1 year and 18% of those 1 to 4 years old are affected by recurrent respiratory

Clinical Outcomes of Bacterial Lysate Therapy in Adult Respiratory Tract Diseases

The effectiveness of bacterial lysate therapy also has been investigated in adults. The Canadian Prevention of Acute Respiratory Infection by an Immunostimulant (PAR-IS) study was a randomized, double-blinded, placebo-controlled trial that assessed whether daily ingestion of OM-85 BV could prevent acute exacerbation of adult COPD. Although the treatment did not decrease the number of acute episodes, it shortened hospitalization by 50% (1.5 vs 3.4 days) and decreased the risk of hospitalization

Applications in Allergy and Asthma

The dysregulation of regulatory T-cell lineages and TH1 and TH2 populations causes undesirable inflammatory responses against self-antigens, gastrointestinal flora, and allergens, contributing to epidemics of non-communicable diseases and autoimmune and allergic phenomena, respectively.[40], [59] Regulatory T cells secrete IL-10 and TGF-β and are present in smaller numbers in individuals with atopy. Bacterial lysates promote TGF-β–mediated development of regulatory T-cell subsets,[14], [22],

Are Bacterial Lysates Safe to Use?

Immunostimulant treatment is limited by the difficulties in obtaining high-quality data and patient safety concerns. The aforementioned Cochrane review found no differences in the frequency of adverse events between immunostimulant-treated and control groups,45 and another study failed to find differences in adverse cutaneous and gastrointestinal reactions in COPD between patients treated with bacterial lysates and those receiving a placebo. A prospective RCT of 54 children younger than 12

Conclusion

Bacterial lysates are used to prevent recurrent respiratory tract infections and acute exacerbation of COPD, although little is currently known about the molecular mechanisms underlying their clinical effects. The most plausible explanation is an IgA antibody response against pathogens at mucosal surfaces and activation of mucosal DCs by TLR-dependent signaling through TLR-2/6 and TLR-9. In addition to proinflammatory cytokine secretion, these mechanisms might provide antiviral coverage.

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    Disclosure: Dr Feleszko has received speaker's honoraria from GSK, Pierre-Fabre Medicament, Ranbaxy, and UCB. The other authors declare no conflicts of interest.

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