表紙・目次 『第15回CEReS国際シンポジウム「環境リモートセンシングのこれま での成果とさらなる挑戦」』 2009年12月15日～16日 於千葉大学

Held on 15-16 December, 2009, Chiba Universit

B cells control maternofetal priming of allergy and tolerance in a murine model of allergic airway inflammation

Background: Allergic asthma is a chronic lung disease resulting from inappropriate immune responses to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Objective: We analyzed the mechanisms of perinatal tolerance induction to allergens, with particular focus on the role of B cells in preconception and early intrauterine immune priming. Methods: Wild-type (WT) and B cell-deficient mice received ovalbumin (OVA) intranasally before mating. Their offspring were analyzed in a murine model of allergic airway inflammation. Results: Although antigen application before conception protected WT progeny from allergy, it aggravated allergic airway inflammation in B cell-deficient offspring. B-cell transfer restored protection, demonstrating the crucial role of B cells in perinatal tolerance induction. Effective diaplacentar allergen transfer was detectable in pregnant WT mice but not in pregnant B-cell knockout dams, and a ntigen concentrations in WT amniotic fluid (AF) were higher than in IgG-free AF of B cell-deficient dams. Application of OVA/IgG immune complexes during pregnancy boosted OVA uptake by fetal dendritic cells (DCs). Fetal DCs in human subjects and mice expressed strikingly higher levels of Fcγ receptors compared with DCs from adults and were highly efficient in taking up OVA/IgG immune complexes. Moreover, murine fetal DCs effectively primed antigen-specific forkhead box P3+ regulatory T cells after in vitro coincubation with OVA/IgG-containing AF. Conclusion: Our data support a decisive role for B cells and immunoglobulins during in utero tolerance priming. These findings improve the understanding of perinatal immunity and might support the development of effective primary prevention strategies for allergy and asthma in the future

Severity of allergic airway disease due to house dust mite allergen is not increased after clinical recovery of lung infection with chlamydia pneumoniae in mice

Chlamydia pneumoniae is associated with chronic inflammatory lung diseases like bronchial asthma and chronic obstructive pulmonary disease. The existence of a causal link between allergic airway disease and C. pneumoniae is controversial. A mouse model was used to address the question of whether preceding C. pneumoniae lung infection and recovery modifies the outcome of experimental allergic asthma after subsequent sensitization with house dust mite (HDM) allergen. After intranasal infection, BALB/c mice suffered from pneumonia characterized by an increased clinical score, reduction of body weight, histopathology, and a bacterial load in the lungs. After 4 weeks, when infection had almost resolved clinically, HDM allergen sensitization was performed for another 4 weeks. Subsequently, mice were subjected to a methacholine hyperresponsiveness test and sacrificed for further analyses. As expected, after 8 weeks, C. pneumoniae-specific antibodies were detectable only in infected mice and the titer was significantly higher in the C. pneumoniae/HDM allergen-treated group than in the C. pneumoniae/NaCl group. Intriguingly, airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid were significantly lower in the C. pneumoniae/HDM allergen-treated group than in the mock/HDM allergen-treated group. We did observe a relationship between experimental asthma and chlamydial infection. Our results demonstrate an influence of sensitization to HDM allergen on the development of a humoral antibacterial response. However, our model demonstrates no increase in the severity of experimental asthma to HDM allergen as a physiological allergen after clinically resolved severe chlamydial lung infection. Our results rather suggest that allergic airway disease and concomitant cellular changes in mice are decreased following C. pneumoniae lung infection in this setting

Bacterial infection triggers exacerbation of established pulmonary fibrosis in mice: Impact on lung protective immunity

Introduction: Patients developing lung fibrosis have an increased risk for recurrent bacterial infections, and bacterial infections per se are considered to be a risk factor for exacerbation of pulmonary fibrosis in humans. We here employed a two-hit model of pulmonary fibrosis and consecutive bacterial pneumonia induced by Streptococcus pneumoniae (Spn) or Klebsiella pneumoniae (Kpn) to characterize lung host defense mechanisms of fibrosing lungs and to examine whether bacterial pneumonia would trigger exacerbation of lung fibrosis in mice. Methods: Mice received intratracheal instillations of an adenoviral vector encoding biologically active transforming growth factor-b1 (TGF b1) for induction of lung fibrosis or control vector. At 7, 14, and 21 days post-treatment, mice were mock-infected or infected with Spn or Kpn, and lung fibrosis was assessed in the absence or presence of bacterial infection by determination of lung collagen contents, Ashcroft scores, and invasive lung function measurements. In addition, bacterial loads were determined in BAL fluid and lung tissue of mice at 24-72 h post-infection. Results: Mice treated with AdTGFb1 developed progressive fibrosis with lung collagen contents increasing by day 7 and peaking by days 14 and 21, overall resulting in decreased lung function. Mice infected with Spn or Kpn exhibited significantly increased lung CFU counts on day 7 but not on day 14 of fibrosis induction, demonstrating that the severity of lung fibrosis itself does not impact on lung protective immunity against bacterial challenge. Importantly, both Spn and Kpn were able to trigger exacerbation of lung fibrosis in mice, which again was accompanied by a further decreased lung function. However, exacerbation of lung fibrosis did not further impair lung protective immunity against Spn or Kpn challenge relative to non-exacerbated lung fibrosis. Conclusion: This is the first report showing that bacterial infections may trigger exacerbation of established lung fibrosis in mice. Moreover, the degree of lung collagen deposition itself does not influence lung protective immunity against major lung-tropic Gram-positive and -negative bacterial pathogens. In this line, Spn- and Kpn-induced exacerbation of lung fibrosis did not further attenuate lung antibacterial responses in mice. This two-hit fibrosis/infection model may allow preclinical evaluation of novel antibacterial/immunomodulatory strategies to inhibit bacterial pathogen-induced exacerbation of lung fibrosis in patients