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 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.
Padrid
P A
PA
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. ppadrid@flowcity.bsd.uchicago.edu
Mathur
M
M
Li
X
X
Herrmann
K
K
Qin
Y
Y
Cattamanchi
A
A
Weinstock
J
J
Elliott
D
D
Sperling
A I
AI
Bluestone
J A
JA
D000069594:Abatacept; D000403:Airway Resistance / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000909:Antibodies, Helminth / Q000097:blood; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000494:pharmacology*; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D060908:CTLA-4 Antigen; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000276:immunology*; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000473:pathology; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL / Q000469:parasitology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D012550:Schistosoma mansoni / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects
D000909:Antibodies, Helminth; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000947:Antigens, Helminth; D016085:Bronchoconstrictor Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D017077:Culture Media, Conditioned; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D000069594:Abatacept