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*
Division of Pulmonary and Critical Care Medicine, and
Division of Rheumatology and Immunology, University of Virginia Health System, Charlottesville, VA 22908;
Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712; and
Center for Comparative Medicine, University of Virginia Health System, Charlottesville, VA 22908
To evaluate the role of CCR2 in allergic asthma, mutant mice deficient in CCR2 (CCR2-/-) and intact mice were sensitized with i.p. OVA with alum on days 0 and 7, and challenged by inhalation with nebulization of either OVA or saline. Airway hyperreactivity, measured by the methacholine-provoked increase in enhanced pause, was significantly increased (p < 0.05) in OVA-challenged CCR2-/- mutant mice, compared with comparably challenged CCR2+/+ mice. OVA-challenged CCR2-/- mutants also were also found to have enhanced bronchoalveolar lavage fluid eosinophilia, peribronchiolar cellular cuffing, and Ig subclass switching, with increase in OVA-specific IgG1 and IgE. In addition, RNase protection assay revealed increased whole lung expression of IL-13 in OVA-challenged CCR2-/- mutants. Unexpectedly, serum monocyte chemotactic protein-1 levels were 8-fold higher in CCR2-/- mutants than in CCR2+/+ mice sensitized to OVA, but OVA challenge had no additional effect on circulating monocyte chemotactic protein-1 in either genotype. Ag stimulation of lymphocytes isolated from OVA-sensitized CCR2 mutants revealed a significant increase (p < 0.05) in IL-5 production, which differed from OVA-stimulated lymphocytes from sensitized CCR2+/+ mice. These experiments demonstrate an enhanced response in airway reactivity and in lung inflammation in CCR2-/- mutant mice compared with comparably sensitized and challenged CCR2+/+ mice. These observations suggest that CC chemokines and their receptors are involved in immunomodulation of atopic asthma.
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