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*
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Biomedical Research Institute, Rockville, MD 20852
To dissect the controversial roles of type 1 and type 2 cytokines
to the pathogenesis of schistosomiasis, we generated IL-10/IL-4- and
IL-10/IL-12-deficient mice that develop highly polarized type 1 and
type 2 cytokine responses, respectively. Interestingly, the
Th1-polarized IL-10/IL-4-deficient mice rapidly lost weight at the
onset of egg-laying and displayed 100% mortality by wk 9
postinfection. This acute mortality was linked to overexpression of the
proinflammatory mediators IFN-
, TNF-
, and inducible NO and the
formation of nonfibrotic granulomas. Elevated serum aspartate
transaminase levels confirmed that mortality was in part attributable
to acute hepatotoxicity. In contrast, the Th2-polarized
IL-10/IL-12-deficient mice developed a progressive wasting disease that
correlated with increased hepatic fibrosis, formation of large
eosinophil-rich granulomas, a 10-fold increase in IL-4 and IL-13, and
significant mortality during the chronic stages of infection.
Surprisingly, IL-10-deficient mice displayed pathological features that
were characteristic of both extremes, while wild-type mice developed
relatively successful long term chronic infections. These data
demonstrate that IL-10 significantly suppresses type 1 and type 2
cytokine development in IL-4- and IL-12-deficient mice, respectively,
thereby impeding the development of severe egg-induced pathology in the
single cytokine-deficient animals. Together, these findings reveal the
central regulatory role of IL-10 in the pathogenesis of schistosomiasis
and illustrate that excessive type 1 and type 2 cytokine responses
trigger distinct, but equally detrimental, forms of pathology following
infection.
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S. M. L. Montenegro, F. G. C. Abath, A. L. C. Domingues, W. G. Melo, C. N. L. Morais, E. M. Coutinho, S. Mahanty, and T. A. Wynn Enhanced Interleukin-12 and CD40 Ligand Activities but Reduced Staphylococcus aureus Cowan 1-Induced Responses Suggest a Generalized and Progressively Impaired Type 1 Cytokine Pattern for Human Schistosomiasis Infect. Immun., November 1, 2002; 70(11): 5903 - 5912. [Abstract] [Full Text] [PDF]
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S. Henri, C. Chevillard, A. Mergani, P. Paris, J. Gaudart, C. Camilla, H. Dessein, F. Montero, N.-E. M. A. Elwali, O. K. Saeed, et al. Cytokine Regulation of Periportal Fibrosis in Humans Infected with Schistosoma mansoni: IFN-{gamma} Is Associated with Protection Against Fibrosis and TNF-{alpha} with Aggravation of Disease J. Immunol., July 15, 2002; 169(2): 929 - 936. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, E. A. Patton, A. C. La Flamme, M. I. Araujo, C. R. Huxtable, B. Bauman, and E. J. Pearce Impaired Th2 Development and Increased Mortality During Schistosoma mansoni Infection in the Absence of CD40/CD154 Interaction J. Immunol., May 1, 2002; 168(9): 4643 - 4649. [Abstract] [Full Text] [PDF]
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D. E. Jones, M. R. Ackermann, U. Wille, C. A. Hunter, and P. Scott Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection Infect. Immun., April 1, 2002; 70(4): 2151 - 2158. [Abstract] [Full Text] [PDF]
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L. R. Schopf, K. F. Hoffmann, A. W. Cheever, J. F. Urban Jr., and T. A. Wynn IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection J. Immunol., March 1, 2002; 168(5): 2383 - 2392. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, M. I. Araujo, and E. J. Pearce Immunology of Parasitic Helminth Infections Infect. Immun., February 1, 2002; 70(2): 427 - 433. [Full Text] [PDF]
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S. K. Lundy and D. L. Boros Fas Ligand-Expressing B-1a Lymphocytes Mediate CD4+-T-Cell Apoptosis during Schistosomal Infection: Induction by Interleukin 4 (IL-4) and IL-10 Infect. Immun., February 1, 2002; 70(2): 812 - 819. [Abstract] [Full Text] [PDF]
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B. Vaillant, M. G. Chiaramonte, A. W. Cheever, P. D. Soloway, and T. A. Wynn Regulation of Hepatic Fibrosis and Extracellular Matrix Genes by the Th Response: New Insight into the Role of Tissue Inhibitors of Matrix Metalloproteinases J. Immunol., December 15, 2001; 167(12): 7017 - 7026. [Abstract] [Full Text] [PDF]
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N. Tsuji, K. Suzuki, H. Kasuga-Aoki, Y. Matsumoto, T. Arakawa, K. Ishiwata, and T. Isobe Intranasal Immunization with Recombinant Ascaris suum 14-Kilodalton Antigen Coupled with Cholera Toxin B Subunit Induces Protective Immunity to A. suum Infection in Mice Infect. Immun., December 1, 2001; 69(12): 7285 - 7292. [Abstract] [Full Text] [PDF]
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A. C. La Flamme, E. A. Patton, and E. J. Pearce Role of Gamma Interferon in the Pathogenesis of Severe Schistosomiasis in Interleukin-4-Deficient Mice Infect. Immun., December 1, 2001; 69(12): 7445 - 7452. [Abstract] [Full Text] [PDF]
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M. K. Park, K. F. Hoffmann, A. W. Cheever, D. Amichay, T. A. Wynn, and J. M. Farber Patterns of Chemokine Expression in Models of Schistosoma mansoni Inflammation and Infection Reveal Relationships between Type 1 and Type 2 Responses and Chemokines In Vivo Infect. Immun., November 1, 2001; 69(11): 6755 - 6768. [Abstract] [Full Text] [PDF]
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J. A. Pedras-Vasconcelos, L. R. Brunet, and E. J. Pearce Profound effect of the absence of IL-4 on T cell responses during infection with Schistosoma mansoni J. Leukoc. Biol., November 1, 2001; 70(5): 737 - 744. [Abstract] [Full Text] [PDF]
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C. G. Lee, R. J. Homer, Z. Zhu, S. Lanone, X. Wang, V. Koteliansky, J. M. Shipley, P. Gotwals, P. Noble, Q. Chen, et al. Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor {beta}1 J. Exp. Med., September 17, 2001; 194(6): 809 - 822. [Abstract] [Full Text] [PDF]
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P. G. Fallon, P. Smith, E. J. Richardson, F. J. Jones, H. C. Faulkner, J. Van Snick, J.-C. Renauld, R. K. Grencis, and D. W. Dunne Expression of Interleukin-9 Leads to Th2 Cytokine-Dominated Responses and Fatal Enteropathy in Mice with Chronic Schistosoma mansoni Infections Infect. Immun., October 1, 2000; 68(10): 6005 - 6011. [Abstract] [Full Text] [PDF]
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