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* Department of Mucosal Immunology and Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139;
Department of Medicine and
Department of Pediatrics, Harvard Medical School,
Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, and
¶ Partners Asthma Center, Boston, MA 02115;
|| Department of Immunology and Oncology, National Center for Biotechnology/Consejo Superior de Investigaciones Cientificas, Campus of Cantoblanco, Madrid, Spain;
# Genetrix, Madrid, Spain; and
** Meakins-Christie Laboratory, McGill University, Montreal, Quebec, Canada
CCL1 is the predominant chemokine secreted from IgE-activated human and mouse mast cells in vitro, colocalizes to mast cells in lung biopsies, and is elevated in asthmatic airways. CCR8, the receptor for CCL1, is expressed by 
70% of CD4+ T lymphocytes recruited to the asthmatic airways, and the number of CCR8-expressing cells is increased 3-fold in the airways of asthmatic subjects compared with normal volunteers. In vivo, CCL1 expression in the lung is reduced in mast cell-deficient mice after aeroallergen provocation. Neutralization of CCL1 or CCR8 deficiency results in reduced mucosal lung inflammation, airway hyperresponsiveness, and mucus hypersecretion to a similar degree as detected in mast cell-deficient mice. Adenoviral delivery of CCL1 to the lungs of mast cell-deficient mice restores airway hyperresponsiveness, lung inflammation, and mucus hypersecretion to the degree observed in wild-type mice. The consequences of CCR8 deficiency, including a marked reduction in Th2 cytokine levels, are comparable with those observed by depletion of CD4+ T lymphocytes. Thus, mast cell-derived CCL1- and CCR8-expressing CD4+ effector T lymphocytes play an essential role in orchestrating lung mucosal inflammatory responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Current address: Altana Research Institute, 610 Lincoln Street, Waltham, MA 02451.
2 Current address: Novartis Institutes, 250 Massachusetts Avenue, Cambridge, MA 02139.
3 Current address: Roche Paolo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304.
4 Current address: McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
5 Current address: Institut National de la Santé et de la Recherche Médicale, Unité 362, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
6 Current address: CombinatoRx, Inc., 245 First Street, Cambridge, MA 02142.
7 Current address: Gene Logic, Inc., 38 Sidney Street, Cambridge, MA 02139.
8 Current address: Hoffmann La-Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110-1199.
9 Current address: Boehringer Ingelheim, Inc., 900 Ridgebury Road, Ridgefield, CT 06877.
10 Current address: Amgen, 2450 Bayshore Parkway, Mountain View, CA 94043.
11 Current address: MedImmune, Inc., One MedImmune Way, Gaithersburg, MD 20878.
12 Address correspondence and reprint requests to Dr. Roland Kolbeck, MedImmune, One MedImmune Way, Gaithersburg, MD 20878. E-mail address: kolbeckr{at}medimmune.com
13 Abbreviations used in this paper: AHR, airway hyperresponsiveness; Penh, enhanced pause; BAL, bronchoalveolar lavage; wt, wild type; AB/PAS, Alcian blue/periodic acid Schiff; DIG, digoxigenin; SCF, stem cell factor; i.n., intranasal(ly).
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