Anti‐interleukin (IL)‐4 and ‐IL‐5 antibodies downregulate IgE and eosinophilia in mice exposed to <i>Aspergillus</i> antigens

Kurup, Viswanath P.; Murali, Pazhayannur S.; Guo, Jun; Choi, Hongyung; Banerjee, Banani; Fink, Jordan N.; Coffman, Robert L.

doi:10.1111/j.1398-9995.1997.tb02526.x

Cited by 43 publications

(52 citation statements)

References 18 publications

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“…However, A. fumigatus-sensitized group 1 and CpG-ODN-treated groups 2 and 3 exhibited comparable allergen-specific IgG1. This finding is in line with our previous results, where anti-IL-4-treated and IL-4 knockout BALB/c mice produced specific IgG1 antibody when exposed to Aspergillus antigen, indicating that IgG1 is not predominantly regulated by IL-4 (13,15).…”

Section: Discussionsupporting

confidence: 82%

Modulation of Airway Inflammation by Immunostimulatory CpG Oligodeoxynucleotides in a Murine Model of Allergic Aspergillosis

Banerjee¹,

Kelly²,

Fink³

et al. 2004

Infect Immun

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Allergic aspergillosis is a Th2 T-lymphocyte-mediated pulmonary complication in patients with atopic asthma and cystic fibrosis. Therefore, any therapeutic strategy that selectively inhibits Th2 T-cell activation may be useful in downregulating allergic lung inflammation in asthma. In the present study, we developed a CpG oligodeoxynucleotide (ODN)-based immune intervention of allergic inflammation in a mouse model of allergic aspergillosis. Four different groups of mice were used in a short-term immunization protocol. Three experimental groups of animals (groups 1 to 3) were sensitized with Aspergillus fumigatus antigens. Animals in group 1 were immunized with A. fumigatus antigen alone, while those in group 2 were treated with CpG-ODN 1 day before the first antigen immunization, and the animals in group 3 received the first CpG-ODN administration between the antigen treatments. The animals in group 4 served as controls and were given phosphate-buffered saline. Allergen-specific serum immunoglobulins and total immunoglobulin E in different groups of animals were measured by enzyme-linked immunosorbent assay, while airway remodeling and cytokine production were studied by immunohistochemistry. The results demonstrated that CpG-ODN administration either before (group 2) or between (group 3) antigen treatments resulted in reduced total immunoglobulin E levels and peripheral blood eosinophil numbers compared to A. fumigatus allergen-sensitized group 1 animals. Similarly, treatment with CpG-ODN also downregulated inflammatory cell infiltration, goblet cell hyperplasia, and basement membrane thickening compared to A. fumigatus-sensitized mice. The distinct reduction in peripheral blood eosinophilia and airway remodeling in CpG-ODN-treated mice emphasized its usefulness as an immunomodulating agent for allergic fungal diseases.

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Section: Discussionsupporting

confidence: 82%

Modulation of Airway Inflammation by Immunostimulatory CpG Oligodeoxynucleotides in a Murine Model of Allergic Aspergillosis

Banerjee¹,

Kelly²,

Fink³

et al. 2004

Infect Immun

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“…A mouse model that recapitulates the hallmarks of human ABPA has been used to dissect which components of the immune response contribute to pathogenesis (15,20). A central role for CD4 ϩ T cells in promoting the pathogenesis of ABPA has been demonstrated (12-14, 25, 29), with the Th2 cytokines IL-4, IL-5, and IL-13 contributing to pulmonary pathology (3,4,23,27,28,38). The factors that determine when CD4 ϩ T cells are activated in response to A. fumigatus exposure and whether the responding T cells will be biased to a Th1 or Th2 phenotype are unknown.…”

mentioning

confidence: 99%

Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

et al. 2005

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Aspergillus fumigatus is an important fungal pathogen that causes invasive pulmonary disease in immunocompromised hosts. Respiratory exposure to A. fumigatus spores also causes allergic bronchopulmonary aspergillosis, a Th2 CD4؉ -T-cell-mediated disease that accompanies asthma. The microbial factors that influence the differentiation of A. fumigatus-specific CD4 ؉ T lymphocytes into Th1 versus Th2 cells remain incompletely defined. We therefore examined CD4؉ -T-cell responses of immunologically intact mice to intratracheal challenge with live or heat-inactivated A. fumigatus spores. Live but not heat-inactivated fungal spores resulted in recruitment of gamma interferon (IFN-␥)-producing, fungus-specific CD4؉ T cells to lung airways, achieving A. fumigatus-specific frequencies exceeding 5% of total CD4 ؉ T cells. While heat-inactivated spores did not induce detectable levels of IFN-␥-producing, A. fumigatus-specific CD4 ؉ T cells in the airways, they did prime CD4؉ T-cell responses in draining lymph nodes that produced greater amounts of interleukin 4 (IL-4) and IL-13 than T cells responding to live conidia. While immunization with live fungal spores induced antibody responses, we found a marked decrease in isotype-switched, A. fumigatus-specific antibodies in sera of mice following immunization with heat-inactivated spores. Our studies demonstrate that robust Th1 T-cell and humoral responses are restricted to challenge with fungal spores that have the potential to germinate and cause invasive infection. How the adaptive immune system distinguishes between metabolically active and inactive fungal spores remains an important question.

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“…Of these cytokines, IL-4 seems to play a key role in the manifestation of the disease. In murine models of fungal allergen-induced airway disease, absence of IL-4 results in suppressed T2 responses and pronounced T1 responses (25,27). Mice treated with anti-IL-4 or anti-IL-4 receptor antibodies and IL-4 Ϫ/Ϫ mice fail to develop most but not all airway changes (8,10,12).…”

Section: Discussionmentioning

confidence: 99%

“…Neutralization of these cytokine mediators in experimental models significantly reduces generation of allergic responses (6,7,27). CD4…”

Section: Discussionmentioning

confidence: 99%

Effect of a CD4-Depleting Antibody on the Development ofCryptococcus neoformans-Induced Allergic Bronchopulmonary Mycosis in Mice

et al. 2006

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Allergic bronchopulmonary mycosis (ABPM) is a hypersensitivity lung disease in which fungal colonization is accompanied by an allergic response to the fungus. Using a mouse model of ABPM caused by Cryptococcus neoformans infection of C57BL/6 mice, the goal of the present studies was to determine the effect of the CD4-depleting monoclonal antibody GK1.5 on the development of the allergic responses seen during active fungal infection. These results would provide insight into the role of CD4 ؉ T cells in this disease. Our results show that GK1.5 treatment resulted in attenuation of pulmonary inflammation and eosinophilia in these animals. These mice also had reduced T2 cytokine production and no serum immunoglobulin E production. Absence of CD4؉ T cells did not affect recruitment of CD8 ؉ T cells to the site of infection; however, the numbers of CD19 ؉ B cells were severely reduced in the lungs of CD4 ؉ T-cell-depleted animals. We also examined changes in the pulmonary architecture and found that depletion of CD4 ؉ T cells was associated with a significant reduction in mucus production and goblet cell metaplasia in these mice. Interestingly, attenuation of Th2 responses in CD4؉ T-cell-depleted animals did not increase the fungal load in their lungs. We also compared development of ABPM in young and mature mice and did not find any differences at any of the time points. Overall, our results show that depletion of CD4 ؉ T cells prevents the development of Th2 responses seen during ABPM.Allergic bronchopulmonary mycosis (ABPM) is a hypersensitivity disease that results when fungal colonization of the lung is accompanied by an allergic response to the fungus. It is typically seen in atopic individuals such as asthmatics and patients with cystic fibrosis. This disease is characterized by several clinical, radiologic, immunologic, and pathological symptoms that range from mild asthma to end-stage fibrotic disease (9, 14, 26). Significant pulmonary pathology is associated with fungus-induced allergic and asthmatic lung disease, characterized by increased Th2 cytokine generation, immunoglobulin E (IgE) and IgG production, eosinophilia, airway hyperresponsiveness, and airway remodeling.In humans, ABPM is caused largely by molds and includes significant involvement of the bronchi, where hyphae can be seen. To date, there is no mouse model that recapitulates all of the aspects of this disease. Aspergillus fumigatus, the most common cause of ABPM in humans, has not been reported to cause the same disease in mice. Allergic responses can be generated by repeated exposure to A. fumigatus antigen or conidia if the animal is primed, but it is impossible to establish A. fumigatus colonization in these mice similar to that seen in humans. In C57BL/6 mice, C. neoformans will induce an allergic response in the lungs and the pulmonary infection becomes chronic with the fungal load driving the allergic response (3,16). This is a very similar response to ABPM in humans, with two notable exceptions: a relative lack of bronchial involvement...

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Anti‐interleukin (IL)‐4 and ‐IL‐5 antibodies downregulate IgE and eosinophilia in mice exposed to Aspergillus antigens

Cited by 43 publications

References 18 publications

Modulation of Airway Inflammation by Immunostimulatory CpG Oligodeoxynucleotides in a Murine Model of Allergic Aspergillosis

Modulation of Airway Inflammation by Immunostimulatory CpG Oligodeoxynucleotides in a Murine Model of Allergic Aspergillosis

Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

Effect of a CD4-Depleting Antibody on the Development ofCryptococcus neoformans-Induced Allergic Bronchopulmonary Mycosis in Mice

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Anti‐interleukin (IL)‐4 and ‐IL‐5 antibodies downregulate IgE and eosinophilia in mice exposed to Aspergillus antigens

Cited by 43 publications

References 18 publications

Modulation of Airway Inflammation by Immunostimulatory CpG Oligodeoxynucleotides in a Murine Model of Allergic Aspergillosis

Modulation of Airway Inflammation by Immunostimulatory CpG Oligodeoxynucleotides in a Murine Model of Allergic Aspergillosis

Distinct CD4+-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia

Effect of a CD4-Depleting Antibody on the Development ofCryptococcus neoformans-Induced Allergic Bronchopulmonary Mycosis in Mice

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Distinct CD4⁺-T-Cell Responses to Live and Heat-InactivatedAspergillus fumigatusConidia