BCG Priming of Dendritic Cells Enhances T Regulatory and Th1 Function and Suppresses Allergen-Induced Th2 Function in vitro and in vivo

Abstract

Background: The inverse correlation of mycobacterial infection with asthma prevalence and the inhibitory effects of vaccination with Bacille Calmette-Guérin (BCG) on airway hyperreactivity in asthma models suggest modulation of dendritic cell (DC) and T cell functions by mycobacterial compounds. Methods: To delineate these immunological effects, the immunogenicity of BCG Copenhagen, BCG Chicago and BCG Pasteur was compared in a mouse model. Bone marrow-derived dendritic cells (BMDCs) from BALB/c mice were stimulated with ovalbumin (OVA) with or without BCG. BMDCs were phenotypically characterized by flow cytometry, and we used ELISA to measure the cytokine production of BMDCs as well as of co-cultivated allergen-specific T cells in response to OVA-pulsed. Immunomodulatory effects of BCG were studied in a model of allergic airway inflammation by adoptive transfer of allergen-pulsed BMDCs. Results: Immunomodulation with BCG induced production of IL-10 and IL-12 by BMDCs. Co-cultured allergen-specific T cells produced less IL-5, IL-13 and IFN-γ but more IL-10. Also the number of FoxP3⁺ regulatory T cells was enhanced. Strongest effects were seen with BCG Chicago and BCG Pasteur. In vivo, administration of BCG modulated OVA-pulsed BMDCs then reduced eosinophilic airway inflammation but enhanced infiltration with granulocytes. Airway hyperreactivity and mucus production were reduced and more FoxP3⁺ T cells were observed. Conclusion: BCG-induced suppression of Th2-type allergic airway inflammation was associated with enhancement of regulatory T cell function but also of Th1-associated neutrophilic airway inflammation. These findings raise concerns regarding the safety profile of BCG as a potential tool for prevention and therapy of allergic airway disease.

Mycobacteria-Infected Dendritic Cells Attract Neutrophils That Produce IL-10 and Specifically Shut Down Th17 CD4 T Cells through Their IL-10 Receptor

“…We show that BCG-infected DCs actively participate in neutrophil recruitment. Consistent with our observations, Ahrens and colleagues (45) have also shown that BCG-infected DCs administered to mouse airways induced strong neutrophil recruitment. Therefore, DCs chronically infected with mycobacteria present in the mature granuloma (9) actively participate in the prolonged recruitment of neutrophils.…”

Vacinação com BCG e redução do risco de asma

“…(21) A study investigating a cohort of low-income children in Salvador, Brazil, reported that the prevalence of asthma attributable to atopy was only 20% and that asthma is most strongly correlated with poor housing conditions and sanitation (unpublished data). One group of authors (15) investigated the effect of BCG vaccination on an experimental model of asthma in mice and confirmed the previous reports of suppression of the Th2 inflammatory response in the airways, accompanied by the activation of regulatory T cells. However, concomitant neutrophilic inflammation related to the stimulation of Th1 cells was also observed.…”

“…Based on this premise, various studies have been conducted in an attempt to identify interventions that might be incorporated into strategies to attenuate or prevent inflammation in asthma. (3,15) In practice, however, this theory is not tenable. Because of the plurality of the immune response, the various inflammatory phenotypes of asthma, the genetic diversity, the environmental diversity and the various opinions regarding the timing of the intervention, this is a complex issue.…”

“…The ability of mycobacteria (which stimulate Th1 lymphocytes and regulatory T cells) to modulate the Th2 response has been documented in vitro and in various models of asthma. (3,15) In a cross-sectional study investigating the impact of BCG vaccination and revaccination on the prevalence of asthma among adolescents in Salvador, Brazil, the overall analysis of the sample of individuals who received one or two doses of the BCG vaccine revealed no significant protection; however, neonatal BCG vaccination provided some protection to individuals who presented with symptoms of chronic rhinitis and who therefore were at a higher risk of developing asthma. (16) A recent meta-analysis of 23 studies concluded that early BCG vaccination was associated with a small reduction in the risk of asthma (OR = 0.86; 95% CI: 0.79-0.93).…”

Der p 2 Recombinant Bacille Calmette-Guérin Targets Dendritic Cells to Inhibit Allergic Airway Inflammation in a Mouse Model of Asthma

“…It was reported that DCs played an important role in BCG infection-mediated inhibition of allergy to ragweed [8]. In addition, intranasal administration of BCG modulated ovalbumin (OVA)-pulsed bone marrow-derived stem cells, increased the number of Foxp3+ cells in bronchial lymph nodes and reduced OVA-induced eosinophilic airway inflammation [9]. Hence, we hypothesized that DCs might also play a central role in Der p 2 rBCG-mediated inhibition of allergic airway inflammation.…”