Effects of combined bacille Calmette-Guérin and dehydroepiandrosterone treatment on established asthma in mice.

Both bacille Calmette-Guerin (BCG) and dehydroepiandrosterone induce Th1 immune responses and suppress Th2 allergic reactions. To investigate whether a combined administration of BCG and dehydroepiandrosterone treat asthma more effectively, BALB/c mice (n = 8 per group) with established airway hyper-responsiveness were treated with BCG and/or dehydroepiandrosterone. Combined treatment with 2 x 10(5) colony-forming units (CFUs) of BCG and 0.01% dehydroepiandrosterone was the most effective one at suppressing eosinophilia in bronchoalveolar lavage fluids. In addition, this combination also was better at suppressing hypersensitivity as compared to BCG alone (13.7 +/- 4.0- versus 3.6 +/- 0.5-fold increase in the sensitivity index; P < .05) in male mice. Similarly, the effect of the combined treatment was superior to that of individual treatments at decreasing the serum ovalbumin-specific immunoglobulin E (IgE) level. However, the addition of 0.1% dehydroepiandrosterone to BCG significantly decreased the efficacy of BCG on hypersensitivity in female mice. In male mice, the suppressive effect of the treatments on hypersensitivity tended to be lower, and the baseline interferon-gamma /interleukin-5 (IFN-gamma /IL-5) ratio in the splenocyte supernatant was significantly higher as compared to female mice. In conclusion, treatment with an appropriate combination of BCG and dehydroepiandrosterone had additive therapeutic effects on mice with established asthma. Androgens in males and dehydroepiandrosterone overdose might reduce the efficacy of BCG.

BCG-induced dendritic cell responses and suppression of interleukin-5 production from T cells in atopic asthmatics.

Bacille Calmette-Guérin (BCG) induces potent Th1 responses with the help of interleukin (IL)-10 and IL-12 released from dendritic cells (DCs), and suppresses Th2- associated allergic reactions. However, there are still some controversies on therapeutic effects of BCG in asthmatics. This study investigated whether BCG administration to DCs suppresses IL-5 production from T cells in atopic asthmatics. DCs derived from peripheral blood of subjects were cultured with or without BCG and Dermatophagoides farinae extract. Some DCs were co-cultured with T cells in the presence of BCG or the above culture supernatants. In the atopic asthmatics, BCG significantly increased IL-10 and IL-12 production from DCs. In the presence of D. farinae extract, BCG further increased IL-10 production. BCG-induced IL-10 production was significantly higher in the atopics (n=14) than in the non-atopics (n=9). Both BCG and the BCG-treated DCs culture supernatant significantly increased IFN-gamma production from T cells. Both BCG and the supernatant from DCs+BCG+D. farinae co-cultures significantly decreased IL-5 production (all p<0.05), but the supernatant from DCs+BCG co-cultures did not. In conclusion, administration of BCG together with D. farinae extract effectively decreased IL-5 production from T cells, probably through the action of IL-10 and IL-12 released from DCs in D. farinae-sensitive asthmatics.

Effects of combined BCG and DHEA treatment in preventing the development of asthma.

Both BCG and dehydroepiandrosterone (DHEA) induce Th1 immune responses and suppress Th2 allergic reactions. To investigate whether the combination of BCG and DHEA has an additive effect on asthma prevention, BALB/c mice (n = 10 per group) were given an intraperitoneal injection of BCG at the beginning of sensitization, and fed mice chow containing DHEA throughout the study. In female mice, the combined administration of 2 x 10(4) CFUs BCG and 0.01% DHEA effectively suppressed the ovalbumin-induced increase in airway sensitivity to methacholine (56.5 vs. 8.2 mg/mL, p < 0.01), while BCG (13.9 mg/mL) or DHEA (17.9 mg/mL) alone did not. However, the addition of high dose (0.1%) DHEA decreased the efficacy of high dose (2 x 10(5) CFUs) BCG in suppressing the airway responsiveness and eosinophilia. In male mice, the treatments with BCG and/or DHEA were less effective, and the interferon-gamma/interleukin-4 ratio in the splenocyte supernatant was significantly higher and the ovalbumin-specific IgE concentration in the serum was significantly lower as compared to female mice. In conclusion, the combination of low doses of BCG and DHEA had an additive effect in suppressing the development of airway hypersensitivity. Androgens in males and DHEA overdose might reduce the efficacy of BCG.

Effects of dehydroepiandrosterone on Th2 cytokine production in peripheral blood mononuclear cells from asthmatics.

BACKGROUND/AIMS: The androgen dehydroepiandrosterone (DHEA) attenuates allergic inflammatory airway reactions by down-regulating the Th2 response in mice. The purpose of this study was to investigate whether DHEA suppresses Th2 cytokine production in cultured peripheral blood mononuclear cells (PBMCs) from asthmatic patients. METHODS: Sixty-one consecutive suspected asthmatic or non-asthmatic men underwent tests for asthma. PBMCs from each subject were cultured with and without DHEA (0.01~10 microM) for 48 h. The concentrations of interferon (IFN)-gamma, interleukin (IL)-5, and IL-10 in the culture supernatant were measured via an enzyme-linked immunosorbent assay. RESULTS: In PBMCs from subjects exhibiting methacholine airway hyperresponsiveness (AHR), DHEA significantly suppressed IL-10, IL-5, and IFN-gamma production in a dose-dependent manner (all p<0.001) and tended to increase the IFN-gamma/IL-5 ratio (p=0.087). DHEA (10 microM) suppressed cytokine production to a greater degree in subjects with AHR compared with those without AHR (IL-5: 24.0+/-7.8% vs. 40.9+/-3.6%, p<0.01; IFN-gamma: 29.7+/-7.0% vs. 54.5+/-5.1%, p<0.01). Cytokine suppression was significantly related to AHR, serum total IgE levels, and skin reactivity to house dust mites. CONCLUSIONS: DHEA suppressed both Th1 and Th2 responses, with a Th1 bias, and the degree of suppression was associated with the severity of AHR or atopy. Therefore, DHEA may be a useful therapy for asthma.

Inoculation route-dependent and allergen-specific suppressive effects of bacille Calmette-Guérin vaccination on asthmatic reactions in BALB/c mice.

Intranasal bacille Calmette-Guérin (BCG) vaccination causes greater suppression of ovalbumin-induced airway eosinophilia in mice than does subcutaneous vaccination. Coadministration of ovalbumin with interleukin (IL)-18 induces an ovalbumin-specific Th1 immune reaction. The purpose of this study was to examine whether the suppressive effect of BCG is dependent on the inoculation method, using various murine asthma models. Female BALB/c mice (n = 7 per group) were immunized with BCG subcutaneously or intranasally, then sensitized with ovalbumin or Dermatophagoides farinae either immediately or one week later. After provocation with one of the allergens, the mice were tested by methacholine bronchial challenge, and analyses of the inflammatory cell numbers in the airways and cytokine levels in the supernatant of concanavalin A-stimulated splenocytes were conducted. Overall, the airway responses to the allergens were significantly lower and the interferon (IFN)-gamma level was significantly higher in BCG-treated mice than in untreated mice, and the number of airway eosinophils was significantly related to the IFN-gamma/IL-5 ratio (r = -0.444, p < 0.001). Subcutaneous BCG inoculation tended to have a greater suppressive effect on the development of airway hyperresponsiveness and eosinophilia than did intranasal inoculation. Concurrent BCG vaccination and D. farinae sensitization one week before ovalbumin sensitization tended to have a greater suppressive effect on airway responsiveness to methacholine induced by D. farinae aerosols than did that induced by ovalbumin aerosols. Subcutaneous BCG inoculation suppressed asthmatic reactions more remarkably than did intranasal inoculation, and concurrent BCG vaccination and allergen sensitization induced allergen-specific suppression of asthmatic reactions.

Strain-dependent suppressive effects of BCG vaccination on asthmatic reactions in BALB/c mice.

BACKGROUND: The choice of BCG vaccine strain may play an important role in vaccination efficiency. OBJECTIVE: To investigate whether the suppressive effects of BCG on asthma depend on the strain of BCG. METHODS: Female BALB/c mice were injected intraperitoneally with 1 of 4 different strains of BCG (1 X 10(6) CFU): Pasteur F1173P2, Tokyo 172, Tice, and Connaught. Seven days later, the animals were sensitized by 2 injections of ovalbumin (20 microg) at 2-week intervals before being provoked with 1% ovalbumin aerosols on 3 successive days. Thereafter, the mice underwent a methacholine bronchial challenge and were killed to quantify the inflammatory cells and cytokines in bronchoalveolar lavage fluid and the supernatant of cultured splenocytes. RESULTS: The eosinophil proportion in the bronchoalveolar lavage fluid was significantly lower and the concentration of interferon-gamma and the interferon-gamma-interleukin 5 (IL-5) ratio in the supernatant of cultured splenocytes were significantly higher in each of the BCG-treated groups (n=10 per group) than in the asthma control group (n=15). However, the methacholine sensitivity (P < .05) and IL-5 concentration (P < .01) in the supernatant of cultured splenocytes were significantly lower only in the group treated with the Tokyo strain of BCG. There was a significant positive correlation between IL-5 and IL-10 concentrations (r = 0.79; P < .001). CONCLUSIONS: The 4 strains of BCG suppressed asthma to different degrees, but all strains induced a shift in the T(H)1/T(H)2 balance toward T(H)1 without increasing IL-10-related regulatory T-cell activity.