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Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
The immunoregulatory functions of IL-4 and IL-5 have identified these cytokines as primary targets for the resolution of airways inflammation and bronchial hyperreactivity in asthma. However, the individual contribution of each of these cytokines and of IL-5-regulated eosinophilia to the induction of airways hyperreactivity in mouse models of asthma remains highly controversial. In this investigation, we have used IL-4- and IL-5-deficient mice of the same genetic background in combination with inhibitory mAbs to these cytokines to identify unequivocally the contribution of these factors to the induction of airways hyperreactivity. Sensitization and aeroallergen challenge of wild-type mice with OVA induced pathological changes to the respiratory epithelium, airways eosinophilia, and hyperreactivity to ß-methacholine. Inhibition of the actions of IL-4 and/or IL-5 did not abolish airways hyperreactivity, and in the case of IL-4-deficient mice pretreated with anti-IL-5 mAb, airways hyperreactivity persisted in the absence of pronounced airways inflammation. Airways hyperreactivity was abolished only by anti-CD4+ mAb treatment. However, aeroallergen challenge of IL-5-/- mice showed that morphologic changes to the airways were critically linked to IL-5 and eosinophilia. This investigation demonstrates the existence in BALB/c mice of a novel CD4+ T cell pathway for modulating airways hyperreactivity. These findings may provide an explanation for the dissociation of airways eosinophilia from the development of airways hyperreactivity observed in some cases of asthma and in animal models of this disease.
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J. C. KIPS, K. G. TOURNOY, and R. A. PAUWELS Gene Knockout Models of Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S66 - 70. [Full Text] [PDF]
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D. C. Webb, A. N. J. McKenzie, A. M. L. Koskinen, M. Yang, J. Mattes, and P. S. Foster Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity J. Immunol., July 1, 2000; 165(1): 108 - 113. [Abstract] [Full Text] [PDF]
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J. G. Karras, K. McGraw, R. A. McKay, S. R. Cooper, D. Lerner, T. Lu, C. Walker, N. M. Dean, and B. P. Monia Inhibition of Antigen-Induced Eosinophilia and Late Phase Airway Hyperresponsiveness by an IL-5 Antisense Oligonucleotide in Mouse Models of Asthma J. Immunol., May 15, 2000; 164(10): 5409 - 5415. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, W. E. Paul, and A. Sher Single Cell Analysis Reveals That IL-4 Receptor/Stat6 Signaling Is Not Required for the In Vivo or In Vitro Development of CD4+ Lymphocytes with a Th2 Cytokine Profile J. Immunol., March 15, 2000; 164(6): 3047 - 3055. [Abstract] [Full Text] [PDF]
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 A. Heinzmann, X.-Q. Mao, M. Akaiwa, R.T. Kreomer, P.-S. Gao, K. Ohshima, R. Umeshita, Y. Abe, S. Braun, T. Yamashita, et al. Genetic variants of IL-13 signalling and human asthma and atopy Hum. Mol. Genet., March 1, 2000; 9(4): 549 - 559. [Abstract] [Full Text] [PDF]
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A. W. Mould, A. J. Ramsay, K. I. Matthaei, I. G. Young, M. E. Rothenberg, and P. S. Foster The Effect of IL-5 and Eotaxin Expression in the Lung on Eosinophil Trafficking and Degranulation and the Induction of Bronchial Hyperreactivity J. Immunol., February 15, 2000; 164(4): 2142 - 2150. [Abstract] [Full Text] [PDF]
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Y. Shibata, L. A. Foster, J. F. Bradfield, and Q. N. Myrvik Oral Administration of Chitin Down-Regulates Serum IgE Levels and Lung Eosinophilia in the Allergic Mouse J. Immunol., February 1, 2000; 164(3): 1314 - 1321. [Abstract] [Full Text] [PDF]
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C. DUEZ, J. KIPS, J. PESTEL, K. TOURNOY, A.-B. TONNEL, and R. PAUWELS House Dust Mite-induced Airway Changes in hu-SCID Mice Am. J. Respir. Crit. Care Med., January 1, 2000; 161(1): 200 - 206. [Abstract] [Full Text]
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M. A. Aronica, A. L. Mora, D. B. Mitchell, P. W. Finn, J. E. Johnson, J. R. Sheller, and M. R. Boothby Preferential Role for NF-{kappa}B/Rel Signaling in the Type 1 But Not Type 2 T Cell-Dependent Immune Response In Vivo J. Immunol., November 1, 1999; 163(9): 5116 - 5124. [Abstract] [Full Text] [PDF]
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 T. R. Johnson and B. S. Graham Secreted Respiratory Syncytial Virus G Glycoprotein Induces Interleukin-5 (IL-5), IL-13, and Eosinophilia by an IL-4-Independent Mechanism J. Virol., October 1, 1999; 73(10): 8485 - 8495. [Abstract] [Full Text] [PDF]
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P. S. Foster Allergic Networks Regulating Eosinophilia Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 451 - 454. [Full Text]
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M. D. Inman, R. Ellis, J. Wattie, J. A. Denburg, and P. M. O'Byrne Allergen-Induced Increase in Airway Responsiveness, Airway Eosinophilia, and Bone-Marrow Eosinophil Progenitors in Mice Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 473 - 479. [Abstract] [Full Text]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, J. M. Ward, A. W. Cheever, W. E. Paul, and A. Sher Schistosome-Infected IL-4 Receptor Knockout (KO) Mice, in Contrast to IL-4 KO Mice, Fail to Develop Granulomatous Pathology While Maintaining the Same Lymphokine Expression Profile J. Immunol., July 1, 1999; 163(1): 337 - 342. [Abstract] [Full Text] [PDF]
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J. A. Wilder, D.D. S. Collie, B. S. Wilson, D. E. Bice, C. Richard Lyons, and M. F. Lipscomb Dissociation of Airway Hyperresponsiveness from Immunoglobulin E and Airway Eosinophilia in a Murine Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., June 1, 1999; 20(6): 1326 - 1334. [Abstract] [Full Text]
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 I.-C. HO, J.I. KIM, S.J. SZABO, and L.H. GLIMCHER Tissue-specific Regulation of Cytokine Gene Expression Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 573 - 584. [Abstract] [PDF]
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G. Grünig, M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick, D. Sheppard, M. Mohrs, D. D. Donaldson, R. M. Locksley, et al. Requirement for IL-13 Independently of IL-4 in Experimental Asthma Science, December 18, 1998; 282(5397): 2261 - 2263. [Abstract] [Full Text]
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