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RANTES (CCL5) Regulates Airway Responsiveness after Repeated Allergen Challenge

Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Erwin W. Gelfand, M.D., Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: gelfande{at}njc.org

RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days 1 and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term–challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated–challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term–challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN- levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-–producing CD4 T cells in lung, and IFN- production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti–IFN-, administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN- and IL-12.

Key Words: airway hyperresponsiveness • IFN- • IL-12 • RANTES (CCL5)

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