Protective effect of Schistosoma mansoni infection on allergic airway inflammation depends on the intensity and chronicity of infection

BACKGROUND: Population studies have suggested that chronic and intense helminth infections, in contrast to acute and mild helminth infections, might suppress allergic airway inflammation. OBJECTIVE: We sought to address the question of how the chronicity and intensity of helminth infections affect allergic airway inflammation in a well-defined experimental model. METHODS: C57/Bl6 mice were infected with Schistosoma mansoni, followed by sensitization and challenge with ovalbumin (OVA), and different stages and intensities of infection were studied. To this end, mice were analyzed at 8, 12, or 16 weeks, representing the acute, intermediate, or chronic phases of infection, respectively. RESULTS: Lung lavage eosinophilia, peribronchial inflammation, and OVA-induced airway hyperresponsiveness were increased during acute infection but significantly decreased when infection progressed into chronicity. Decreases in lung lavage eosinophilia were parasite density-dependent. Similar levels of OVA-specific IgE were found during all phases of infection, whereas both OVA-specific and parasite-specific T(H)2 cytokine levels were significantly reduced during chronic infection. Inhibition of airway inflammation could be transferred to OVA-sensitized recipient mice by B cells and CD4(+) T cells from spleens of chronically, but not acutely, infected mice. This suppression was IL-10-dependent. CONCLUSION: During chronic, but not acute, helminth infections, suppressive mechanisms are induced that regulate immune reactions to inhaled allergens. These data confirm human epidemiologic observations in a well-controlled animal model. CLINICAL IMPLICATIONS: Characterization of chronic helminth infection-induced regulatory mechanisms will help in the development of future therapeutics to treat or prevent allergic disease.     

Opposite effects of immunotherapy with ovalbumin and the immunodominant T-cell epitope on airway eosinophilia and hyperresponsiveness in a murine model of allergic asthma.

In the present study, we investigated immunotherapy using an entire protein or an immunodominant epitope in a murine model of allergic asthma. Immunotherapy was performed in ovalbumin (OVA)-sensitized mice before OVA challenge. Mice were treated subcutaneously with OVA, the immunodominant epitope OVA323-339, or vehicle. In vehicle-treated animals, repeated OVA challenge induced increased serum levels of OVA-specific immunoglobulin (Ig)G1, IgE, airway eosinophilia, and hyperresponsiveness, compared with saline-challenged animals. In addition, interleukin (IL)-4 and IL-5 production upon OVA restimulation of lung-draining lymph node cells in vitro were significantly increased in OVA-challenged animals. Immunotherapy using OVA significantly reduced airway eosinophilia and hyperresponsiveness. This finding was accompanied by significantly reduced OVA-specific IL-4 and IL-5 production. Further, OVA immunotherapy induced increased serum levels of OVA-specific IgG1, whereas OVA-specific IgG2a and IgE levels were not affected. In contrast to OVA immunotherapy, immunotherapy with OVA323-339 aggravated airway eosinophilia and hyperresponsiveness. OVA-specific IgG1, IgG2a, and IgE serum levels, and in vitro IL-4 and IL-5 production, were not affected. Thus, immunotherapy with protein resulted in beneficial effects on airway eosinophilia and hyperresponsiveness, which coincided with a local reduced T-helper 2 (Th2) response. In contrast, peptide immunotherapy aggravated airway hyperresponsiveness and eosinophilia, indicating a local enhanced Th2 response.     

Dissociation of specific and total IgE antibody responses following repeated low-level infections with Nippostrongylus brasiliensis in rats.

IgE, IgG and mast cell responses were studied in rats infected weekly with 10 larvae of Nippostrongylus brasiliensis (NB). Worm recovery at 8 weeks of repeated infections was six-fold greater than that of a single infection with 10 larvae, suggesting the accumulation of worms during the repeated infections. Total serum IgE was increased after 2 weeks of infection, and further increased after repeated infections: at 6 weeks of infection the level was four to six times higher than that after a single infection. Anti-NB IgG1 levels were also significantly higher after repeated infections than after a single infection. On the other hand, there was no significant difference in the level of anti-NB IgE between single and repeated infections, as determined by ELISA, as well as by passive cutaneous anaphylaxis (PCA) reaction. Mastocytosis was induced in the small intestine after both single and repeated infections, but the levels did not differ between the two. These results indicate that total IgE and specific IgG1 production are augmented by repeated helminth infections, but specific IgE and mast cell responses are not. This pattern of response may minimize the development of IgE-dependent hypersensitivity reactions with repeated helminth infections.     

Infection of mice with the helminth Strongyloides stercoralis suppresses pulmonary allergic responses to ovalbumin

Asthma and helminth infections induce similar immune responses characterized by the presence of peripheral blood eosinophilia and elevated serum IgE levels. Epidemiological surveys have reported either increases or decreases in the development of atopic diseases and asthma based on the prevalence of helminth infections in the population. The aim of this study was to determine if a pre-existing helminth infection would increase or decrease subsequent allergic responses to an unrelated allergen in the lungs. BALB/cByJ mice were infected with the nematode parasite Strongyloides stercoralis prior to ovalbumin (OVA) immunization and intratracheal challenge. Bronchoalveolar lavage (BAL) and fluid (BALF) were collected 3 days post-challenge and cellular and humoral immune responses were measured. Intracellular cytokine staining revealed increased IL-4 and IL-5 producing cells in BAL from mice infected with S. stercoralis before OVA sensitization. Increased IL-5 protein levels and decreased IFN-gamma protein levels were also observed in the BALF. There was, however, no increase in airway eosinophil accumulation in mice infectd with parasites before sensitization with OVA as compared to mice exposed to OVA alone. Furthermore, eotaxin levels in the lungs induced by OVA was suppressed in mice infected with the parasite before OVA sensitization. The development of OVA specific IgE responses in BALF was also impaired in mice infected with the parasite before sensitization with OVA. These results suggest that a pre-existing helminth infection may potentiate a systemic Type 2-type response yet simultaneously suppress in the lungs allergen-specific IgE responses and eotaxin levels in response to subsequent exposure to allergens.     

Chronic inhaled ovalbumin exposure induces antigen-dependent but not antigen-specific inhalational tolerance in a murine model of allergic airway disease

Sensitized mice acutely challenged with inhaled ovalbumin (OVA) develop allergic airway inflammation, characterized by OVA-specific IgE production, airway eosinophilia, increased pulmonary B and T lymphocytes, and airway hyperreactivity. In this study, a chronic exposure model was developed and two distinct patterns of response were observed. Discontinuous inhalational exposure to OVA (6 weeks) produced airway inflammation and hyperreactivity that were similar to acute (10 days) responses. Continuous inhalational exposure to OVA (6 or 11 weeks) resulted in attenuation of airway eosinophilia and hyperresponsiveness without reduction of OVA-specific IgE and IgG(1) levels. The inhibition of airway inflammation was dependent on continuous exposure to antigen, because continuously exposed mice with attenuated inflammatory responses redeveloped allergic airway disease if the OVA aerosols were interrupted and then restarted (11-week-discontinuous). Inhalational tolerance induced by continuous OVA exposure demonstrated bystander suppression of cockroach allergen-mediated airway eosinophilia. These findings may be attributed to changes in production of the anti-inflammatory cytokine interleukin-10 during continuous OVA aerosol exposure. The symptomatic and asymptomatic allergic responses in human asthmatics could be explained by similar variable or discontinuous exposures to aeroantigens.     

Interference between host resistance to Listeria monocytogenes infection and ovalbumin-induced allergic responses in mice

Listeria monocytogenes promotes the induction of the T-helper 1 (Th1) cell response, while ovalbumin (OVA) induces a Th2 cell response and allergic reactions, such as airway hyperreactivity and immunoglobulin E (IgE) production. When mice were immunized with OVA on day 7 after L. monocytogenes infection, eosinophilia in bronchoalveolar lavage and the production of total IgE, OVA-specific IgE, interleukin-4 (IL-4), and IL-5 in the circulation were markedly suppressed. Cytokine responses, including IL-4, IL-5, IL-10, IL-13, and gamma interferon, to OVA were decreased in the spleen cell cultures obtained from OVA-immunized mice that had been infected with L. monocytogenes. Conversely, when OVA-immunized mice were infected with L. monocytogenes, conversion from the nonlethal infection to the lethal infection occurred. Host resistance to L. monocytogenes infection in OVA-immunized mice was enhanced by the administration of anti-IL-10 monoclonal antibody. The present study indicates that striking interference is observed between Th1-inducing L. monocytogenes infection and Th2-driven OVA-induced airway hyperreactivity.     

Chymase inhibitor ameliorates eosinophilia in mice infected with Nippostrongylus brasiliensis

BACKGROUND: Chymase is a chymotrypsin-like serine protease primarily stored in mast cells. Infection with helminth parasites is known to increase the level of mast cell chymase in the jejunum and serum in mice. The aim of the present study is to elucidate the role of chymase in helminth infection. METHODS: Chymase inhibitor SUN-C8257 was administered to mice infected with the nematode Nippostrongylus brasiliensis, and the number of eosinophils in the blood, serum IgE levels and fecal egg counts were determined. RESULTS: Administration of SUN-C8257 significantly inhibited blood eosinophilia in BALB/c mice infected with N. brasiliensis. The effect of SUN-C8257 was specific for eosinophils, in that it affected neither the number of total leukocytes nor serum IgE levels. SUN-C8257 did not alter the fecal egg counts in this model, showing that SUN-C8257 has no effect on infectivity and expulsion of the nematode. N. brasiliensis infection induced eosinophilia in mast cell-deficient mice (W/W(v)) as well as their littermates (+/+), and SUN-C8257 inhibited the eosinophilia in +/+ mice but not in W/W(v) mice. These results suggest that the eosinophil number may be regulated by different mechanisms in W/W(v) and +/+ mice, and that the effect of SUN-C8257 on nematode-induced eosinophilia is probably due to chymase inhibition. CONCLUSIONS: Chymase released by activated mast cells may play a role in helminth-induced eosinophilia.     

Regulation and biological function of helminth-induced cytokine responses.

The immunological hallmarks of infection with parasitic helminths, namely eosinophilia, mastocytosis and increased IgE synthesis, all appear to be induced by cytokines from the TH2 subset of CD4+ T cells: IgE production is stimulated by interleukin 4 (IL-4), eosinophilia by IL-5 and mastocytosis by IL-3 and IL-4. Here, Fred Finkelman and colleagues argue that the functional significance of the eosinophilia-mastocytosis-IgE axis in helminth infection is unclear and suggest that in some worm infections TH2-cell cytokines may contribute to host protection, while in others they may promote parasite survival.     

OVA-Fc融合基因疫苗对哮喘小鼠的疗效观察

目的探讨OVA-Fc融合基因疫苗治疗哮喘小鼠气道炎症和气道高反应性的效果。方法分别将制备的OVA-Fc-pcDNA3．1质粒、OVA-pcDNA3．1质粒、pcDNA3．1质粒,皮下免疫Balb／c哮喘小鼠模型,40d后,观察肺组织的病理变化,并检测肺泡灌洗液中细胞总数及嗜酸粒细胞计数,细胞因子的含量以及血清中OVA特异的IgE抗体的水平。结果OVA-Fc-pcDNA3．1基因修饰的DNA疫苗免疫小鼠后,能有效抑制哮喘小鼠肺组织的炎细胞浸润,肺泡灌洗液中细胞总数明显下降（P〈0．05）,嗜酸性粒细胞的总数明显下降（P〈0．05）,肺泡灌洗液中IL-10、INF-Y的分泌增加（P〈0．05）,血清中OVA特异的IgE抗体能有效的得以控制（P〈0．05）。结论OVA-Fc-pcDNA3．1基因修饰的DNA疫苗可较OVA变应原基因更强的特异性地抑制哮喘小鼠的气道炎症,有望对哮喘的治疗具有重要的价值。     

Dose-dependent effects of endotoxins on allergen sensitization and challenge in the mouse

BACKGROUND: Levels of endotoxins greatly differ according to environmental settings. OBJECTIVE: To study the effect of lipopolysaccharide (LPS) at increasing doses (0.1-1000 ng) on allergen sensitization and challenge in the mouse. METHODS: Mice were sensitized systemically and challenged locally with ovalbumin (OVA) in the presence or absence of LPS. Inflammation was assessed by determining total and differential cell counts and T-helper type 2 (Th)2 cytokine (IL-4 and IL-5) levels in bronchoalveolar lavage fluid (BALF). Total and OVA-specific IgE levels were quantified in serum. Airway hyper-responsiveness (AHR) was assessed by whole-body barometric plethysmography. RESULTS: Administered prior to sensitization, LPS at 100 or 1000 ng dose-dependently decreased allergen- induced total and OVA-specific IgE, airway eosinophilia and Th2 cytokines in BALF, without changing AHR. Administered during OVA challenge, LPS at 1 ng (an infra-clinical dose) or 100 ng (a dose triggering neutrophilia) enhanced airway eosinophilia, without affecting IgE levels or AHR. CONCLUSION: Our data clearly demonstrate that exposure to LPS influences allergen-induced IgE production and airway eosinophilia in a time and dose-dependent manner, preventing IgE production and development of eosinophilia when administered during allergen sensitization at high doses, and inducing exacerbation of eosinophilia when administered upon allergen challenge at low doses, including infra-clinical doses.     

Blockade of CTLA-4 promotes airway inflammation in naive mice exposed to aerosolized allergen but fails to prevent inhalation tolerance

In subjects not developing allergy, inhalation of nonpathogenic protein antigens causes no harm and is associated with tolerance induction. Repeated exposure to aerosolized ovalbumin (OVA) likewise does not evoke airway inflammation and induces inhalation tolerance in experimental animals. The present study explored the role of the inhibitory T-cell receptor CTLA-4, in preventing inflammation and in establishing inhalation tolerance in response to a protein antigen. Naive BALB/c mice were injected intraperitoneally with anti-CTLA-4 monoclonal antibody or control immunoglobulin G (IgG) and exposed daily to aerosolized saline or OVA over 10 or 20 consecutive days. OVA-specific IgE levels and the inflammatory response in airway tissues were assessed 2 days after last exposure. The OVA-specific IgE response was also evaluated in mice subjected to a subsequent immunogenic OVA challenge 18 days after last aerosol exposure. Additional mice were made tolerant by 10 days of OVA aerosol exposure and were then subjected to an immunogenic OVA challenge combined with CTLA-4 blockade or control IgG treatment. Repeated inhalation of aerosolized OVA alone did not cause a pulmonary inflammatory response. In contrast, 10 days of OVA exposure combined with blockade of CTLA-4 led to development of eosinophilic lung infiltrates, BAL fluid eosinophilia, goblet cell hyperplasia and increased OVA-specific IgE. By 20 days of OVA exposure and blockade of CTLA-4, the inflammatory response remained. Mice exposed to aerosolized OVA for 10 days exhibited greatly reduced OVA-specific IgE responses to subsequent immunogenic OVA challenge. Blockade of CTLA-4 during the period of OVA aerosol exposure did not prevent this suppression of the OVA-specific IgE response. Neither did blockade of CTLA-4 during immunogenic OVA challenge alter the allergen-specific IgE response. Our results indicate that in vivo blockade of CTLA-4 modulates the initial immune response to a protein antigen allowing the development of allergen-induced airway inflammation in naive mice. However, this initial exaggerated immune response is followed by the induction of inhalation tolerance, demonstrating that CTLA-4 signalling is not decisive in this process. Our findings also show that once inhalation tolerance is established it may not be disrupted by blockade of CTLA-4.     

Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response.

During infection, parasites evade the host immune system by modulating or exploiting the immune system; e.g., they suppress expression of major histocompatibility complex class II molecules or secrete cytokine-like molecules. However, it is not clear whether helminths disturb the immune responses of their hosts by controlling the antigen-processing pathways of the hosts. In this study, we identified a new cysteine protease inhibitor, nippocystatin, derived from excretory-secretory (ES) products of an intestinal nematode, Nippostrongylus brasiliensis. Nippocystatin, which belongs to cystatin family 2, consists of 144 amino acids and is secreted as a 14-kDa mature form. In vivo treatment of ovalbumin (OVA)-immunized mice with recombinant nippocystatin (rNbCys) profoundly suppressed OVA-specific proliferation of splenocytes but not non-antigen-specific proliferation of splenocytes. OVA-specific cytokine production was also greatly suppressed in rNbCys-treated mice. Although the serum levels of both OVA-specific immunoglobulin G1 (IgG1) and IgG2a were not affected by rNbCys treatment, OVA-specific IgE was preferentially downregulated in rNbCys-treated mice. In vitro rNbCys inhibited processing of OVA by lysosomal cysteine proteases from the spleens of mice. Mice with anti-nippocystatin antibodies became partially resistant to infection with N. brasiliensis. Based on these findings, N. brasiliensis appears to skillfully evade host immune systems by secreting nippocystatin, which modulates antigen processing in antigen-presenting cells of hosts.     

Mice vaccinated with allergen-pulsed myeloid dendritic cells are not protected from developing allergen-induced Th2 responses

BACKGROUND: Dendritic cells (DC) play a decisive role in the induction of allergen-induced Th1 and Th2 responses. Since the induction of allergen-specific Th1 responses has shown to inhibit allergen-induced Th2-type inflammation, in this study we investigated whether manipulated myeloid-derived DC pulsed with the specific allergen would predominantly induce allergen-specific Th1 responses thereby reducing the development of Th2 responses. METHODS: Murine bone marrow (BM)-DC were generated and pulsed with ovalbumin (OVA) and CpG oligodeoxynucleotides (CpG-ODN). Langerhans cells (LC) were also isolated and pulsed in vitro with OVA. Subsequently, mice were vaccinated intravenously with either CpG/OVA-pulsed BM-DC or OVA-pulsed LC, and the protocol to induce OVA-specific Th2 responses using OVA/alum sensitization was initiated. Airway inflammation and OVA-specific serum antibody levels were evaluated 6 days after the intranasal challenge with OVA. RESULTS: The application ofCpG/OVA-pulsed BM-DC was unable to reduce airway eosinophilia and inflammation in OVA/alum-immunized mice. OVA-specific IgG1 or IgE serum levels were also not reduced. The experiments using LC pulsed with OVA yielded similar results. However, mice vaccinated with CpG/OVA-pulsed BM-DC had greatly enhanced levels of serum OVA-specific IgG2a, suggesting the induction of allergen-specific Th1 responses in vivo. Moreover, allergen-induced mast cell degranulation was decreased using this approach. CONCLUSIONS: Taken together, our results demonstrated that the vaccination with OVA-pulsed BM-DC matured with CpG-ODN or OVA-pulsed LC did not result in a reduction in allergen-specific Th2 responses in a murine model of severe atopic asthma. Other DC-based vaccination strategies should be evaluated in order to prevent the development of allergic disorders.     

Infection with the roundworm Toxocara canis leads to exacerbation of experimental allergic airway inflammation

Background Epidemiological studies performed in developing as well as in western countries suggest that infection with Toxocara canis contributes to the development of atopic diseases. Objectives To investigate the association between infection with this helminth and allergy, we examined the effect of T. canis infection on experimental allergic airway inflammation. Methods BALB/c mice were infected by oral administration with 500 embryonated T. canis eggs followed by ovalbumin (OVA) sensitization and challenge to induce allergic airway inflammation. Results Infection with T. canis in combination with OVA treatment leads to exacerbation of pulmonary inflammation, eosinophilia, airway hyperresponsiveness, OVA specific and total IgE. Relative quantification of cytokine expression in the lungs of these mice showed increased expression of IL‐4 compared with mice that were only T. canis infected or OVA treated. Increased expression of IL‐5 and IL‐10 was measured in the lungs of T. canis‐infected or OVA‐treated mice compared with controls; however, combining infection and OVA treatment did not significantly change the expression of these cytokines. Conclusion A previous infection with T. canis leads to exacerbation of experimental allergic airway inflammation. These results have important consequences for findings on the helminths–allergy association. Several factors, including parasite species, infection of definitive vs. accidental host, parasite load and timing of infection, may influence whether an infection with helminths protects one from or enhances allergic manifestations.     

Resistance to Paracoccidioides brasiliensis infection is linked to a preferential Th1 immune response, whereas susceptibility is associated with absence of IFN-gamma production.

The secretion of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, IL-5, and IL-10 by antigen-stimulated lymph node cells, eosinophil maturation, and the antibody isotypes produced were examined during intraperitoneal infection of susceptible (B10.A) and resistant (A/Sn) mice with Paracoccidioides brasiliensis. Lymph node cells from resistant mice produced early and sustained levels of IFN-gamma and IL-2, whereas susceptible animals secreted low to undetectable amounts of these type 1 cytokines. Both mouse strains presented late and transient production of IL-4, whereas IL-10 was produced constantly throughout the course of disease. Resistant animals produced increasing levels of IL-5 in the chronic phase of the infection (from the eighth week on), whereas susceptible mice showed two peaks of IL-5 production, at the first and twelfth weeks after infection. Only the susceptible strain presented medullary and splenic eosinophilia concomitant with the raised IL-5 production. In resistant mice, the levels of IgG2a antibodies were significantly higher than those observed in susceptible mice, which preferentially secreted IgG2b and IgA isotypes. Taken together, these results demonstrate that a sustained production of IFN-gamma and IL-2 and a predominant secretion of IgG2a antibodies are associated with resistance to P. brasiliensis. In contrast, the production of low levels of IFN-gamma, early secretion of high levels of IL-5 and IL-10, eosinophilia, and a preferential secretion of IgG2b and IgA isotypes characterize the progressive disease in susceptible animals.     

Human Onchocerciasis and Tetanus Vaccination: Impact on the Postvaccination Antitetanus Antibody Response

To investigate whether helminth infections may affect the efficacy of vaccines by impairing the immune response to nonparasite vaccine antigens, we compared the antibody responses to tetanus toxoid (TT) after tetanus vaccination in 193 subjects with Onchocerca volvulus infection with 85 comparable noninfected controls. After vaccination, the proportions of subjects in each group attaining protective levels of antitetanus antibodies were similar (96.9% infected versus 97.6% noninfected). Postvaccination increases in antitetanus immunoglobulin G (IgG) and the predominant IgG isotype, IgG1, were equivalent in both groups, as were increases in specific IgG4 and IgE; however, significantly greater increases in specific IgG2 (P < 0.05) and IgG3 (P < 0.001) were observed in the noninfected group. Stratification of the O. volvulus-infected group into two groups representing light and heavy infections revealed a significantly impaired antitetanus IgG response in those with heavy infections compared to those with light infections (P < 0.01) or no infection (P < 0.05). The impact of concurrent intestinal helminth infections on the antitetanus response was also examined; an increased IgG4/IgE ratio was seen in those infected with Strongyloides stercoralis (P < 0.05) and when all helminth infections were combined as a single group (P < 0.05). These findings indicate that concurrent infection with O. volvulus does not prevent the development of a protective antitetanus response, although heavier O. volvulus infections are able to alter the magnitude of this response, and concurrent helminth infections (O. volvulus and intestinal helminths) may alter TT-specific antibody isotype responses.     

Blockade of CTLA-4 enhances allergic sensitization and eosinophilic airway inflammation in genetically predisposed mice

CTLA-4 (CD152) expression is restricted to subsets of activated T lymphocytes and shares homology with CD28. CTLA-4 and CD28 molecules both bind to B7 molecules on antigen-presenting cells. Whereas CD28-B7 interaction enhances T cell activation, cytokine production and survival, CTLA-4 signaling down-regulates T cell responses. Here, we studied the involvement of CTLA-4 triggering in the pathogenesis of allergen-induced airway inflammation in mice. Anti-CTLA-4 mAb were injected during i.p. sensitization with ovalbumin (OVA). This treatment favored OVA-specific IgE production and augmented blood eosinophilia in BALB/c mice. In BALB/c mice, enhanced Th2 sensitization after anti-CTLA-4 mAb injections resulted in more severe airway inflammation, and increased airway hyperresponsiveness to metacholine, bronchial eosinophilia and IL-4 and IL-5 levels in broncho-alveolar lavage (BAL) fluid following repeated allergen inhalations. Importantly, aggravation of airway inflammation and enhancement of Th2 responses were accompanied by a significant reduction of pulmonary TGF-beta levels at protein level in BAL fluid as well as on mRNA level in inflamed lung tissue. In contrast to BALB/c mice, blockade of CTLA-4 did not alter IgE production nor the phenotype of airway inflammation or TGF-beta production in C57BL/6 mice. Our data suggest that CTLA-4 triggering represents an important regulatory mechanism for Th2 sensitization in genetically predisposed mice by modulating TGF-beta production.     

Time sequence of airway remodeling in a mouse model of chronic asthma: the relation with airway hyperresponsiveness

During the course of establishing an animal model of chronic asthma, we tried to elucidate the time sequence of airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and associated cytokines. Seven-week-old female BALB/c mice were studied as a chronic asthma model using ovalbumin (OVA). After sensitization, mice were exposed twice weekly to aerosolized OVA, and were divided into three groups depending on the duration of 4 weeks, 8 weeks, and 12 weeks. At each time point, airway responsiveness, inflammatory cells, cytokines in bronchoalveolar lavage fluids (BALF), serum OVA-specific IgE, IgG1, IgG2a, and histological examination were carried out. AHR to methacholine, increased levels of OVA-specific IgG1 and IgG2a, and goblet cell hyperplasia were continuously sustained at each time point of weeks. In contrast, we observed a time-dependent decrease in serum OVA-specific IgE, BALF eosinophils, BALF cytokines such as IL-13, transforming growth factor-beta1, and a time-dependent increase in BALF promatrix metalloproteinase-9 and peribronchial fibrosis. In this OVA-induced chronic asthma model, we observed airway remodelings as well as various cytokines and inflammatory cells being involved in different time-dependent manners. However, increased airway fibrosis did not directly correlate with a further increase in airway hyperresponsiveness.     

Prior Bordetella pertussis infection modulates allergen priming and the severity of airway pathology in a murine model of allergic asthma

BACKGROUND: It has been proposed that T helper (Th)2-driven immune deviation in early life can be countered by Th1 inducing childhood infections and that such counter-regulation can protect against allergic asthma. OBJECTIVE: To test whether Th1-inducing infection with Bordetella pertussis protects against allergic asthma using well-characterized murine models. METHODS: Groups of mice were sensitized to ovalbumin (OVA) in the presence or absence of B. pertussis, a well-characterized Th1 inducing respiratory infection. Immunological, pathological and physiological parameters were measured to assess the impact of infection on immune deviation and airway function. RESULTS: We demonstrate that OVA sensitization does not affect the development of B. pertussis-specific immune responses dominated by IgG2a and IFN-gamma and does not impair Th1-mediated clearance of airway infection. In contrast, B. pertussis infection at the time of sensitization modulated the response to OVA and significantly reduced total serum and OVA-specific IgE. The pattern of cytokine responses, in particular OVA-specific IL-5 responses in the spleen was also modulated. However, B. pertussis did not cause global suppression as IL-10 and IL-13 levels were enhanced in OVA-stimulated spleen cell cultures and in lavage fluid from infected co-sensitized mice. Histopathological examination revealed that B. pertussis infection prior to OVA sensitization resulted in increased inflammation of bronchiolar walls with accompanying hyperplasia and mucous metaplasia of lining epithelia. These pathological changes were accompanied by increased bronchial hyper-reactivity to methacholine exposure. CONCLUSION: Contrary to the above premise, a Th1 response induced by a common childhood infection does not protect against bronchial hyper-reactivity, but rather exacerbates the allergic asthmatic response, despite modulation of immune mediators.     

Chlamydia trachomatis infection inhibits airway eosinophilic inflammation induced by ragweed.

While much progress has been achieved in controlling infectious diseases, there is a startling increase in the prevalence of allergic disorders in developed countries. Previous studies using experimental murine models of asthma have demonstrated that mycobacterial infections are capable of suppressing asthma-like reactions induced by ovalbumin (OVA). Using a different intracellular bacterium, Chlamydia trachomatis mouse pneumonitis (MoPn), we examined the effect of infection on the development of allergic responses to a common natural airborne allergen, ragweed (RW). The data showed that airway eosinophilia induced by ragweed sensitization/challenge was significantly reduced in MoPn-infected mice. MoPn-infected mice also exhibited significantly lower levels of allergen-driven Th2 cytokine production, namely IL-4, IL-5, IL-10, and IL-13, following ragweed exposure in comparison with those treated with ragweed only. Additionally, the production of eotaxin, a C-C chemokine for eosinophil chemoattraction following RW exposure, was significantly reduced in the lungs of MoPn-infected mice. However, MoPn infection did not reduce the levels of RW-specific IgE and IgG1 production in the sera, nor did it diminish the level of total serum IgE. These data provide evidence that the suppression of the allergic airway inflammation induced by a common environmental allergen is attainable through intracellular bacterial infection.