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Am. J. Respir. Cell Mol. Biol., Volume 18, Number 4, April, 1998 453-462

CTLA4Ig Inhibits Airway Eosinophilia and Hyperresponsiveness by Regulating the Development of Th1/Th2 Subsets in a Murine Model of Asthma

Philip A. Padrid, Mudit Mathur, Xiantang Li, Karin Herrmann, Yimin Qin, Ashok Cattamanchi, Joel Weinstock, David Elliott, Anne I. Sperling, and Jeffrey A. Bluestone

Asthma, Allergy and Immunology Disease Research Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology, Ben May Institute for Cancer Research, and the Committees on Immunology, and Comparative Medicine and Pathology, Division of the Biological Sciences, The University of Chicago, Chicago, Illinois; and Department of Medicine, University of Iowa, Iowa City, Iowa

Complete T-cell activation requires two distinct signals, one delivered via the T-cell receptor, and the second "co-stimulatory" signal through CD28/B7 ligation. Previous studies showed that the blockade of CD28/B7 ligation alters differentiation of Th1/Th2 lymphocyte subsets in vitro and in vivo. The present study was designed to determine the effect of a CD28/B7 antagonist (CTLA4Ig) on Th1/Th2 development in Schistosoma mansoni-sensitized and airway-challenged mice. Treatment of mice with CTLA4Ig beginning 1 wk after sensitization abolished airway responsiveness to intravenous methacholine determined 96 h following antigen challenge. We also found a significant reduction in bronchoalveolar lavage (BAL) eosinophilia, and reduced peribronchial eosinophilic infiltration and mucoid-cell hyperplasia. Furthermore, CTLA4Ig treatment significantly decreased interleukin (IL)-4 and IL-5 content in BAL fluid in vivo, and the production of IL-5 by lung lymphocytes stimulated with soluble egg antigen (SEA) in vitro. In contrast, the content of interferon-gamma in BAL fluid and supernatant from SEA-stimulated lung lymphocytes from CTLA4Ig-treated mice was increased significantly compared with untreated animals. Thus, CTLA4Ig inhibits eosinophilic airway inflammation and airway hyperresponsiveness in S. mansoni-sensitized and airway-challenged mice, most likely due to attenuated secretion of Th2-type cytokines and increased secretion of Th1-type cytokines.




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