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. 2011 Aug;121(8):3088-93.
doi: 10.1172/JCI45041.

VSports在线直播 - Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells

Isabelle C Arnold  1 , Nina Dehzad, Sebastian Reuter, Helen Martin, Burkhard Becher, Christian Taube, Anne Müller
Affiliations

Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells

Isabelle C Arnold et al. J Clin Invest. 2011 Aug.

Abstract

Atopic asthma is a chronic disease of the airways that has taken on epidemic proportions in the industrialized world. The increase in asthma rates has been linked epidemiologically to the rapid disappearance of Helicobacter pylori, a bacterial pathogen that persistently colonizes the human stomach, from Western societies. In this study, we have utilized mouse models of allergic airway disease induced by ovalbumin or house dust mite allergen to experimentally examine a possible inverse correlation between H. pylori and asthma. H VSports手机版. pylori infection efficiently protected mice from airway hyperresponsiveness, tissue inflammation, and goblet cell metaplasia, which are hallmarks of asthma, and prevented allergen-induced pulmonary and bronchoalveolar infiltration with eosinophils, Th2 cells, and Th17 cells. Protection against asthma was most robust in mice infected neonatally and was abrogated by antibiotic eradication of H. pylori. Asthma protection was further associated with impaired maturation of lung-infiltrating dendritic cells and the accumulation of highly suppressive Tregs in the lungs. Systemic Treg depletion abolished asthma protection; conversely, the adoptive transfer of purified Treg populations was sufficient to transfer protection from infected donor mice to uninfected recipients. Our results thus provide experimental evidence for a beneficial effect of H. pylori colonization on the development of allergen-induced asthma. .

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Figures (V体育ios版)

Figure 1
Figure 1. Experimentally induced asthma is alleviated by H. pylori infection.
Mice were orally infected as neonates (iN) or adults (iA) with H. pylori and sensitized with alum-adjuvanted OVA (A–G) or HDM (H–M) 4 and 6 weeks after infection along with an uninfected (uninf) group. 1 group of neonatally infected mice received antibiotic therapy between the first and second allergen doses. 2 weeks after the second sensitization, all mice (including a mock-sensitized control group [PBS]) were exposed to 3 consecutive daily doses of aerosolized OVA or intranasal HDM. (A, H) Airway hyperresponsiveness in response to increasing doses of methacholine and the highest dose of 100 mg/ml, respectively (upper and lower panels in A). (B, C, I, and J) Tissue inflammation and goblet cell metaplasia as assessed on H&E- and PAS-stained tissue sections. Representative micrographs are shown in B and I; inflammation and PAS scores are shown in C and J. Original magnification, ×100 (H&E); ×400 (PAS). (D and K) Total cells contained in 1 ml of BALF. (E) Relative representation of the indicated cell types in BALF. (F and L) Absolute numbers of eosinophils in 1 ml of BALF. (G and M) IL-5 and/or IL-13 secretion as assessed by cytometric bead array. *P < 0.05 and **P < 0.01 in comparison with uninfected, but allergen-treated, controls. All group data of methacholine measurements are presented as mean ± SEM. Total cell and eosinophil counts in BALF are presented for individual mice, with horizontal bars indicating group medians. Inflammation scores and PAS+ cells are represented by box and whisker plots, with horizontal bars representing medians and whisker ends indicating minimal and maximal values. Cytokine measurements and PCR results are presented as group mean ± SD.
Figure 2
Figure 2. Tregs and semimature DCs accumulate in the lungs of neonatally infected mice.
Groups of mice treated as described in Figure 1 were analyzed with respect to lung infiltration by FoxP3+ Tregs and CD11c+B220– DCs. (A and B) Representative scatter plots and quantification of CD4+FoxP3+ cells in lung preparations of 4–6 mice per group; percentages in A denote the fraction of CD4+FoxP3+ cells of all lung cells. (C) foxP3 expression of the mice shown in B, normalized to GAPDH. (D and E) Representative scatter plots and quantification of CD11c+B220– DCs expressing high and intermediate levels of MHCII; percentages in D denote the fractions of MHCIIhi and MHCIIint cells of all CD11c+B220– lung DCs. (F) Ratios of MHCIIhi/MHCIIint DCs as calculated per mouse. All group data of methacholine measurements are presented as mean ± SEM. Total cell and eosinophil counts in BALF are presented for individual mice, with horizontal bars indicating group medians. Inflammation scores and PAS+ cells are represented by box and whisker plots, with horizontal bars representing medians and whisker ends indicating minimal and maximal values. Cytokine measurements and PCR results are presented as group mean ± SD.
Figure 3
Figure 3. Asthma protection is conferred by Tregs.
Groups of mice were sensitized with OVA or PBS only prior to intravenously receiving unsorted (total [tot]) MLN/PP populations isolated from uninfected or neonatally infected and/or OVA-sensitized or Treg-depleted (–FoxP3+) donors. Tregs were depleted in foxP3-EGFP-DTR–transgenic donors by a single dose of diphtheria toxin 1 day prior to cell isolation; Treg-proficient donors were nontransgenic littermates. Additional recipients received 2.5 × 105 immunomagnetically isolated, MLN/PP-derived CD4+CD25+ Tregs or CD4+CD25– T cells (>85% purity each) from neonatally infected donors. All recipients as well as control groups were nebulized with OVA on days 2, 3, and 4 after adoptive transfer and sacrificed 2 days later. (A) Airway hyperresponsiveness in response to increasing doses of inhaled methacholine and the highest dose of 100 mg/ml, respectively. (B and C) Total cells and eosinophils contained in 1 ml of BALF. (D and E) Tissue inflammation and goblet cell metaplasia as assessed on H&E- and PAS-stained tissue sections. Micrographs of representative T cell recipients and controls are shown in D; inflammation and PAS scores are shown in E for all mice. Original magnification: ×100 (H&E); ×400 (PAS). All group data of methacholine measurements are presented as mean ± SEM. Total cell and eosinophil counts in BALF are presented for individual mice, with horizontal bars indicating group medians. Inflammation scores and PAS+ cells are represented by box and whisker plots, with horizontal bars representing medians and whisker ends indicating minimal and maximal values. Cytokine measurements and PCR results are presented as group mean ± SD.
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