CTLA4IG INHIBITS AIRWAY EOSINOPHILIA AND HYPERRESPONSIVENESS BY REGULATING THE DEVELOPMENT OF TH1 TH2 SUBSETS IN A MURINE MODEL OF ASTHMA/

Complete T-cell activation requires two distinct signals, one delivere d via the T-cell receptor, and the second ''co-stimulatory'' signal th rough CD28/B7 ligation. Previous studies showed that the blockade of C D28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets i n vitro and in vivo. The present study was designed to determine the e ffect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schi stosoma mansoni-sensitized and airway-challenged mice. Treatment of mi ce with CTLA4Ig beginning 1 wk after sensitization abolished airway re sponsiveness to intravenous methacholine determined 96 h following ant igen challenge. We also found a significant reduction in bronchoalveol ar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic i nfiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatmen t significantly decreased interleukin (IL)-4 and IL-5 content in BAL f luid in vivo, and the production of IL-5 by lung lymphocytes stimulate d with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lun g lymphocytes from CTLA4Ig-treated mice was increased significantly co mpared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic air way inflammation and airway hyperresponsiveness in S. mansoni-sensitiz ed and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines.