Enhanced airway Th2 response after allergen challenge in mice deficient inCC chemokine receptor-2 (CCR2)

To evaluate the role of CCR2 in allergic asthma, mutant mice deficient in C CR2 (CCR2(-/-)) and intact mice were sensitized with Lp. OVA with alum on d ays 0 and 7, and challenged by inhalation with nebulization of either OVA o r saline. Airway hyperreactivity, measured by the methacholine-provoked inc rease in enhanced pause, was significantly increased (p < 0.05) in OVA-chal lenged CCR2(-/-) mutant mice, compared with comparably challenged CCR2(+/+) mice. OVA-challenged CCR2(-/-) mutants also were also found to have enhanc ed bronchoalveolar lavage fluid eosinophilia, peribronchiolar cellular cuff ing, and Ig subclass switching, with increase in OVA-specific IgG, and IgE. In addition, RNase protection assay revealed increased whole lung expressi on of IL-13 in OVA-challenged CCR2(-/-) mutants. Unexpectedly, serum monocy te chemotactic protein-1 levels were 8-fold higher in CCR2(-/-) mutants tha n in CCR2(+/+) mice sensitized to OVA, but OVA challenge bad no additional effect on circulating monocyte chemotactic protein-1 in either genotype. Ag stimulation of lymphocytes isolated from OVA-sensitized CCR2 mutants revea led a significant increase (p < 0.05) in IL-5 production, which differed fr om OVA-stimulated lymphocytes from sensitized CCR2(+/+) mice. These experim ents demonstrate an enhanced response in airway reactivity and in lung infl ammation in CCR2(-/-) mutant mice compared with comparably sensitized and c hallenged CCR2(+/+) mice. These observations suggest that CC chemokines and their receptors are involved in immunomodulation of atopic asthma.