BCG priming of dendritic cells enhances T regulatory and Th1 function and suppresses allergen-induced Th2 function in vitro and in vivo.

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. 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. 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-gamma 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. 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.

Ahrens B ，Gruber C ，Rha RD ，Freund T ，Quarcoo D ，Awagyan A ，Hutloff A ，Dittrich AM ，Wahn U ，Hamelmann E ... -  《-》

Lipopolysaccharide stimulation of dendritic cells induces interleukin-10 producing allergen-specific T cells in vitro but fails to prevent allergic airway disease.

Ahrens B ，Freund T ，Rha RD ，Dittrich AM ，Quarcoo D ，Hutloff A ，Hamelmann E ... -  《-》

Vaccinations with T-helper type 1 directing adjuvants have different suppressive effects on the development of allergen-induced T-helper type 2 responses.

Trujillo-Vargas CM ，Mayer KD ，Bickert T ，Palmetshofer A ，Grunewald S ，Ramirez-Pineda JR ，Polte T ，Hansen G ，Wohlleben G ，Erb KJ ... -  《CLINICAL AND EXPERIMENTAL ALLERGY》

Chlamydial respiratory infection during allergen sensitization drives neutrophilic allergic airways disease.

Horvat JC ，Starkey MR ，Kim RY ，Beagley KW ，Preston JA ，Gibson PG ，Foster PS ，Hansbro PM ... -  《-》

Local treatment with BPPcysMPEG reduces allergic airway inflammation in sensitized mice.

According to the hygiene hypothesis, triggering the immune system with microbial components during childhood balances the inherent Th2 bias. In contrast, specific immunotherapy involves exposure of the patient to the allergen in order to achieve desensitization to subsequent contact. In a human in vitro allergy model the potential of the TLR2/6 agonist BPPcysMPEG to modulate antigen presenting cells and allergen-specific immune responses was evaluated. Specific immunomodulation via co-administration of the allergen and BPPcysMPEG enhanced expression of co-stimulatory molecules on DC and increased secretion of the proinflammatory cytokine TNF-α. Acting as an adjuvant, BPPcysMPEG elevated allergen-specific immune responses in co-culture with autologous lymphocytes. Although administration of BPPcysMPEG alone enhanced expression of co-stimulatory molecules on DC, proliferation of autologous lymphocytes was not induced. Based on this finding, the potential of BPPcysMPEG to reduce allergic airway inflammation by preventive modulation of the innate immune system via TLR2/6 agonization was investigated in mice. Local administration of BPPcysMPEG altered cellular influx and cell composition in BAL fluid. Furthermore, the Th2-associated cytokines IL-4 and IL-5 were diminished. Allergen-specific restimulation of cells from mediastinal lymph nodes and splenocytes suggested an alteration of immune responses. The treatment with BPPcysMPEG induced a Th1-dominated cytokine milieu in mediastinal lymph nodes, while allergen-specific immune responses in splenocytes were diminished. The co-administration of allergen and BPPcysMPEG reduced cytokine secretion upon restimulation in mediastinal lymph nodes and splenocytes. From these data we conclude that BPPcysMPEG was able to influence the immune system with regard to subsequent allergen contact by TLR2/6 agonization.

Knothe S ，Mutschler V ，Rochlitzer S ，Winkler C ，Ebensen T ，Guzman CA ，Hohlfeld J ，Braun A ，Muller M ... -  《-》