Cyclophosphamide augments inflammation by reducing immunosuppression in a mouse model of allergic airway disease
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S. Rolph, Michael
A. Cooley, Margaret
A. Sewell, William
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Abstract
Background Allergic asthma is a TH2 cell-driven immunological disease, characterized by eosinophilic inflammation. The cytotoxic agent cyclophosphamide paradoxically augments several immune responses. Objective We studied the proposal that cyclophosphamide may aggravate airway inflammation in allergic mice, and these features might result from the loss of regulatory T cells. Methods BALB/c mice were immunized with ovalbumin on days 0 and 14 and challenged with aerosolized ovalbumin from days 21 to 27. Some mice also received cyclophosphamide on days -2 and 12. Results In the lungs of cyclophosphamide-treated animals, pronounced worsening of inflammatory features was noted, including increased eosinophil infiltration, epithelial thickness, mucus occlusion, and eosinophil numbers in bronchoalveolar lavage fluid. There was also increased total and ovalbumin-specific serum IgE, increased IL-4 and IL-5 secretion by peritracheal lymph node cells, and reduced lung mRNA expression of IL-10 and TGF-ߠin animals treated with cyclophosphamide. The expression of FoxP3, a marker of regulatory T cells, was significantly reduced in lymphoid organs after the second injection of cyclophosphamide, and in the lung tissue after allergen challenge in cyclophosphamide-treated mice. Lung IL-10+CD4+ T cells and cytotoxic T lymphocyte-associated antigen 4+CD4+ T cells were reduced after allergen challenge in cyclophosphamide-treated mice. Conclusion Cyclophosphamide worsened features of allergic pulmonary inflammation in this model, in association with increased production of IgE and TH2 cytokines. The reduced expression of FoxP3 and immunosuppressive cytokines by cyclophosphamide is consistent with the possibility that toxicity to regulatory T cells may contribute to the increased inflammation.
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Journal of Allergy and Clinical Immunology
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117
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3
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Cellular Immunology
Immunology