DIFFERENTIAL RECRUITMENT OF LEUKOCYTE POPULATIONS AND ALTERATION OF AIRWAY HYPERREACTIVITY BY C-C FAMILY CHEMOKINES IN ALLERGIC AIRWAY INFLAMMATION

Allergic airway inflammation is characterized by peribronchial leukocy te accumulation within the airway. Subsequent tissue damage leading to airway hyperreactivity is a result of activation of multiple leukocyt e populations, Using an established model of allergic airway inflammat ion induced by intratracheal challenge with parasite (Schistosoma mans oni egg Ag in presensitized mice, we have examined differential leukoc yte recruitment, These studies have identified key chemokines involved in the accumulation of specific subsets of cells and the induction of airway hyperreactivity. In this study we have examined three C-C fami ly chemokines, MCP-1, MIP-1 alpha, and RANTES, which promote mononucle ar cell- and eosinophil-specific recruitment to the airway. The in viv o neutralization of either MIP-1 alpha or RANTES, but not MCP-1, signi ficantly reduced the intensity of the eosinophil recruitment to the lu ng and airway during the allergic airway response by >50 and >60%, res pectively, In contrast, neutralization of MCP-1 significantly reduced total leukocyte migration (>50% reduction), whereas neutralization of RANTES and MIP-1 alpha had no significant affect on the overall leukoc yte migration. Further examination of the effect of MCP-1 depletion in dicated that both CD4(+) and CD8(+) lymphocyte subsets were decreased, Depletion of MCP-1 significantly reduced the airway hyperreactivity t o near control levels, whereas depletion of MIP-1 alpha or RANTES did not affect the intensity of airway hyperreactivity, These data indicat e that multiple C-C chemokines are involved in the recruitment of part icular leukocyte populations and that neutralization of MCP-1, but not RANTES or MIP-1 alpha, significantly reduced airway hyperreactivity.