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Science 295 (5553): 336-338

Copyright © 2002 by the American Association for the Advancement of Science

Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet

Susetta Finotto,1 Markus F. Neurath,2 Jonathan N. Glickman,3 Shixin Qin,4 Hans A. Lehr,5 Francis H. Y. Green,6 Kate Ackerman,1 Kathleen Haley,1 Peter R. Galle,7 Susanne J. Szabo,8 Jeffrey M. Drazen,18 George T. De Sanctis,1 Laurie H. Glimcher8*

Human asthma is associated with airway infiltration by T helper 2 (TH2) lymphocytes. We observed reduced expression of the TH1 transcription factor, T-bet, in T cells from airways of patients with asthma compared with that in T cells from airways of nonasthmatic patients, suggesting that loss of T-bet might be associated with asthma. Mice with a targeted deletion of the T-bet gene and severe combined immunodeficient mice receiving CD4+ cells from T-bet knockout mice spontaneously demonstrated multiple physiological and inflammatory features characteristic of asthma. Thus, T-bet deficiency, in the absence of allergen exposure, induces a murine phenotype reminiscent of both acute and chronic human asthma.

1 Critical Care and Pulmonary Division,
2 Division of Gastroenterology,
3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4 Millenium Pharmaceuticals, Cambridge, MA 02138, USA.
5 Department of Pathology, University of Mainz, Mainz 55131, Germany.
6 Department of Pathology and Laboratory Medicine University of Calgary, Alberta, Canada T2N 4N1.
7 Medical Clinic I, University of Mainz, Mainz 55131, Germany.
8 Harvard School of Public Health and Harvard Medical School, Harvard Medical School, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail lglimche{at}hsph.harvard.edu

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PNAS 100, 15818-15823
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Lymphotoxin Is Required for Maintaining Physiological Levels of Serum IgE That Minimizes Th1-mediated Airway Inflammation.
H.-S. Kang, S. E. Blink, R. K. Chin, Y. Lee, O. Kim, J. Weinstock, T. Waldschmidt, D. Conrad, B. Chen, J. Solway, et al. (2003)
J. Exp. Med. 198, 1643-1652
   Abstract »    Full Text »    PDF »
Rhinovirus-induced Interferon-{gamma} and Airway Responsiveness in Asthma.
G. D. Brooks, K. A. Buchta, C. A. Swenson, J. E. Gern, and W. W. Busse (2003)
168, 1091-1094
   Abstract »    Full Text »    PDF »
Genetic Reprogramming of Primary Human T Cells Reveals Functional Plasticity in Th Cell Differentiation.
M. S. Sundrud, S. M. Grill, D. Ni, K. Nagata, S. S. Alkan, A. Subramaniam, and D. Unutmaz (2003)
J. Immunol. 171, 3542-3549
   Abstract »    Full Text »    PDF »
Transgenic Overexpression of GATA-3 in T Lymphocytes Improves Autoimmune Glomerulonephritis in Mice with a BXSB/MpJ-Yaa Genetic Background.
K. Yoh, K. Shibuya, N. Morito, T. Nakano, K. Ishizaki, H. Shimohata, M. Nose, S. Izui, A. Shibuya, A. Koyama, et al. (2003)
J. Am. Soc. Nephrol. 14, 2494-2502
   Abstract »    Full Text »    PDF »
T-bet expression is upregulated in active Behcet's disease.
B Li, P Yang, H Zhou, Z Zhang, C Xie, X Lin, X Huang, and A Kijlstra (2003)
Br J Ophthalmol 87, 1264-1267
   Abstract »    Full Text »    PDF »
Effect of Promoter Methylation on the Regulation of IFN-{gamma} Gene During In Vitro Differentiation of Human Peripheral Blood T Cells into a Th2 Population.
S. Yano, P. Ghosh, H. Kusaba, M. Buchholz, and D. L. Longo (2003)
J. Immunol. 171, 2510-2516
   Abstract »    Full Text »    PDF »
Drug Development for Asthma.
M. J. Holtzman (2003)
29, 163-171
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor {alpha} Negatively Regulates T-bet Transcription Through Suppression of p38 Mitogen-Activated Protein Kinase Activation.
D. C. Jones, X. Ding, T. Y. Zhang, and R. A. Daynes (2003)
J. Immunol. 171, 196-203
   Abstract »    Full Text »    PDF »
T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells.
M. AKDIS, A. TRAUTMANN, S. KLUNKER, I. DAIGLE, U. C. KUCUKSEZER, W. DEGLMANN, R. DISCH, K. BLASER, and C. A. AKDIS (2003)
FASEB J 17, 1026-1035
   Abstract »    Full Text »    PDF »
T Cells of Atopic Asthmatics Preferentially Infiltrate Into Human Bronchial Xenografts in SCID Mice.
K. Tsumori, H. Kohrogi, E. Goto, N. Hirata, S. Hirosako, K. Fujii, M. Ando, O. Kawano, and H. Mizuta (2003)
J. Immunol. 170, 5712-5718
   Abstract »    Full Text »    PDF »
IL-6 Production by Pulmonary Dendritic Cells Impedes Th1 Immune Responses.
I. L. Dodge, M. W. Carr, M. Cernadas, and M. B. Brenner (2003)
J. Immunol. 170, 4457-4464
   Abstract »    Full Text »    PDF »
Measuring lung function in mice: the phenotyping uncertainty principle.
J. H. T. Bates and C. G. Irvin (2003)
J Appl Physiol 94, 1297-1306
   Abstract »    Full Text »    PDF »
IgE Cross-Linking or Lipopolysaccharide Treatment Induces Recruitment of Th2 Cells to the Lung in the Absence of Specific Antigen.
R. Stephens and D. D. Chaplin (2002)
J. Immunol. 169, 5468-5476
   Abstract »    Full Text »    PDF »
A reevaluation of the validity of unrestrained plethysmography in mice.
L. K. A. Lundblad, C. G. Irvin, A. Adler, and J. H. T. Bates (2002)
J Appl Physiol 93, 1198-1207
   Abstract »    Full Text »    PDF »
Modeling Allergic Asthma in Mice: Pitfalls and Opportunities.
R. K. Kumar and P. S. Foster (2002)
27, 267-272
   Abstract »    Full Text »

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