Aspergillus fumigatusAntigen Exposure Results in Pulmonary Airway Resistance in Wild-Type but Not in IL-4 Knockout Mice

Kurup, Viswanath P.; Xia, Jinqi; Rickaby, D. A.; Dawson, Chistopher A; Choi, Hongyung; Fink, Jordan N.

doi:10.1006/clim.1998.4656

Cited by 17 publications

(17 citation statements)

References 23 publications

(38 reference statements)

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“…Experimental studies in mice have revealed that IL-4 and IL-5 have unique roles in the development of lung pathology due to Aspergillus. Accordingly, IL-4 Ϫ/Ϫ mice exhibited similar lung inflammation as their wild-type counterparts but completely lacked airway hyperresponsiveness to bronchial spasmogens (36). In another murine study of acute aspergillosis, eosinophilia resulted from the induction of IL-5 by soluble A. fumigatus Ags (37).…”

Section: Discussionmentioning

confidence: 95%

Enhanced Pulmonary Allergic Responses toAspergillusin CCR2−/− Mice

Blease¹,

Mehrad

Standiford

et al. 2000

The Journal of Immunology

146

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Allergic responses to Aspergillus species exacerbate asthma and cystic fibrosis. The natural defense against live Aspergillus fumigatus spores or conidia depends on the recruitment and activation of mononuclear and polymorphonuclear leukocytes, events that are dependent on chemotactic cytokines. In this study, we explored the relative contribution of the monocyte chemoattractant protein-1 receptor, CCR2, in the pulmonary response to A. fumigatus conidia. Following sensitization to soluble A. fumigatus Ags, mice lacking CCR2 due to targeted deletion were markedly more susceptible to the injurious effects of an intrapulmonary challenge with live conidia compared with mice that expressed CCR2 or CCR2+/+. CCR2−/− mice exhibited a major defect in the recruitment of polymorphonuclear cells, but these mice also had significantly more eosinophils and lymphocytes in bronchoalveolar lavage samples. CCR2−/− mice also had significant increases in serum levels of total IgE and whole lung levels of IL-5, IL-13, eotaxin, and RANTES compared with CCR2+/+ mice. Airway inflammation, hyper-responsiveness to spasmogens, and subepithelial fibrosis were significantly enhanced in CCR2−/− mice compared with CCR2+/+ mice after the conidia challenge. Thus, these findings demonstrate that CCR2 plays an important role in the immune response against A. fumigatus, thereby limiting the allergic airway inflammatory and remodeling responses to this fungus.

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Section: Discussionmentioning

confidence: 95%

Enhanced Pulmonary Allergic Responses toAspergillusin CCR2−/− Mice

Blease¹,

Mehrad

Standiford

et al. 2000

The Journal of Immunology

146

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“…This finding coincides with findings from our laboratory (41, 42) and others (43,44) that have shown that MCP-1 controls the Th2 response. Furthermore, although IL-4 does not mediate the lung pathology, it has a major effect on the airway hyperresponsiveness associated with another murine model of allergic aspergillosis (45,46). Thus, subsequent to its antifungal effects, MCP-1/CCL2 contributes to the airway hyperresponsiveness-associated conidia-induced allergic airway disease.…”

Section: Discussionmentioning

confidence: 98%

Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure toAsperigillus fumigatusConidia

Blease¹,

Mehrad

Lukacs³

et al. 2001

The Journal of Immunology

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Asperigillus fumigatus spores or conidia are quickly eliminated from the airways of nonsensitized individuals but persist in individuals with allergic pulmonary responsiveness to fungus. A. fumigatus-induced allergic airway disease is characterized by persistent airway hyperreactivity, inflammation, and fibrosis. The present study explored the role of CCR2 ligands in the murine airway response to A. fumigatus conidia. Nonsensitized and A. fumigatus-sensitized CBA/J mice received an intratracheal challenge of A. fumigatus conidia, and pulmonary changes were analyzed at various times after conidia. Whole lung levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), but neither MCP-3/CCL7 nor MCP-5/CCL12, were significantly elevated at days 3 and 7 after conidia in nonsensitized mice. MCP-1/CCL2 was significantly increased in lung samples from A. fumigatus-sensitized mice at days 14 and 30 after a conidia challenge. Administration of anti-MCP-1/CCL2 antiserum to nonsensitized mice for14 days after the conidia challenge attenuated the clearance of conidia and significantly increased airway hyperreactivity, eosinophilia, and peribronchial fibrosis compared with nonsensitized mice that received conidia and normal serum. Adenovirus-directed overexpression of MCP-1/CCL2 in A. fumigatus-sensitized mice markedly reduced the number of conidia, airway inflammation, and airway hyperresponsiveness at day 7 after the conidia challenge in these mice. Immunoneutralization of MCP-1/CCL2 levels in A. fumigatus-sensitized mice during days14–30 after the conidia challenge did not affect the conidia burden but significantly reduced airway hyperreactivity, lung IL-4 levels, and lymphocyte recruitment into the airways compared with the control group. These data suggest that MCP-1/CCL2 participates in the pulmonary antifungal and allergic responses to A. fumigatus conidia.

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“…Inflammatory responses of the airways are characterized by cellular infiltration of eosinophils and T lymphocytes expressing Th2 cytokines as well as extensive airway remodeling (9,14,15). Recent studies have shown that bacterial DNA carrying non methylated CpG motifs can be used as vaccine adjuvant to selectively induce Th1-dominated immune responses and therefore might be useful as an immunomodulatory agents to treat or prevent undesired Th2-dominant immune responses, such as in allergic disorders (5,7).…”

Section: Discussionmentioning

confidence: 99%

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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Aspergillus fumigatusAntigen Exposure Results in Pulmonary Airway Resistance in Wild-Type but Not in IL-4 Knockout Mice

Cited by 17 publications

References 23 publications

Enhanced Pulmonary Allergic Responses toAspergillusin CCR2−/− Mice

Enhanced Pulmonary Allergic Responses toAspergillusin CCR2−/− Mice

Antifungal and Airway Remodeling Roles for Murine Monocyte Chemoattractant Protein-1/CCL2 During Pulmonary Exposure toAsperigillus fumigatusConidia

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

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