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*
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201; and
Department of Medicine, Harvard Medical School, Boston, MA 02115
The development of Schistosoma mansoni ova-induced
granulomas is regulated by cytokines secreted by distinct Th cell
subsets. To determine the importance of Th1 and Th2 cells in granuloma
formation, we have studied the immune response to S.
mansoni ova in Stat4- and Stat6-deficient mice, which lack Th1
and Th2 cells, respectively. Lymphocytes from both naive and infected
Stat6-deficient mice produced minimal levels of Th2 cell cytokines and
Ag-specific IgG1 and IgE, but showed enhanced production of IFN-
and
Ag-specific IgG2a and IgG2b following schistosome egg injection. This
shift away from a Th2 cell-mediated immune response was coupled with
the development of pulmonary and hepatic granulomas that were greatly
decreased in size compared with those in control littermates. Hepatic
granulomas in Stat6-deficient mice were composed of predominantly
mononuclear cells with very sparse appearance of eosinophils, and their
diminished size was accompanied by decreased amounts of liver
hydroxyproline content as a measure of collagen deposition. In
contrast, lymphocytes from infected Stat4-deficient mice produced Th2
cell cytokines in amounts comparable to those produced by control
littermates, but low levels of IFN-. While infected Stat4-deficient
mice developed pulmonary granulomas following schistosome egg injection
that were modestly impaired in size, the granuloma size and amount of
collagen deposition in the liver were equivalent to those seen in
control littermates. These studies demonstrate that Th2 cells are
required for the full development of the granulomas and
tissue-destructive fibrotic pathology associated with the immune
response to S. mansoni ova.
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M. Hesse, M. Modolell, A. C. La Flamme, M. Schito, J. M. Fuentes, A. W. Cheever, E. J. Pearce, and T. A. Wynn Differential Regulation of Nitric Oxide Synthase-2 and Arginase-1 by Type 1/Type 2 Cytokines In Vivo: Granulomatous Pathology Is Shaped by the Pattern of L-Arginine Metabolism J. Immunol., December 1, 2001; 167(11): 6533 - 6544. [Abstract] [Full Text] [PDF]
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L. I. Rutitzky, H. J. Hernandez, and M. J. Stadecker Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection PNAS, October 16, 2001; (2001) 231258498. [Abstract] [Full Text] [PDF]
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K. Blease, C. Jakubzick, J. Westwick, N. Lukacs, S. L. Kunkel, and C. M. Hogaboam Therapeutic Effect of IL-13 Immunoneutralization During Chronic Experimental Fungal Asthma J. Immunol., April 15, 2001; 166(8): 5219 - 5224. [Abstract] [Full Text] [PDF]
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A. Matsukawa, M. H. Kaplan, C. M. Hogaboam, N. W. Lukacs, and S. L. Kunkel Pivotal Role of Signal Transducer and Activator of Transcription (Stat)4 and Stat6 in the Innate Immune Response during Sepsis J. Exp. Med., March 19, 2001; 193(6): 679 - 688. [Abstract] [Full Text] [PDF]
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K. K. Tekkanat, H. F. Maassab, D. S. Cho, J. J. Lai, A. John, A. Berlin, M. H. Kaplan, and N. W. Lukacs IL-13-Induced Airway Hyperreactivity During Respiratory Syncytial Virus Infection Is STAT6 Dependent J. Immunol., March 1, 2001; 166(5): 3542 - 3548. [Abstract] [Full Text] [PDF]
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A. C. La Flamme, E. A. Patton, B. Bauman, and E. J. Pearce IL-4 Plays a Crucial Role in Regulating Oxidative Damage in the Liver During Schistosomiasis J. Immunol., February 1, 2001; 166(3): 1903 - 1911. [Abstract] [Full Text] [PDF]
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S. Zhang, V. A. Lawless, and M. H. Kaplan Cytokine-Stimulated T Lymphocyte Proliferation Is Regulated by p27Kip1 1 J. Immunol., December 1, 2000; 165(11): 6270 - 6277. [Abstract] [Full Text] [PDF]
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M. Hesse, A. W. Cheever, D. Jankovic, and T. A. Wynn NOS-2 Mediates the Protective Anti-Inflammatory and Antifibrotic Effects of the Th1-Inducing Adjuvant, IL-12, in a Th2 Model of Granulomatous Disease Am. J. Pathol., September 1, 2000; 157(3): 945 - 955. [Abstract] [Full Text] [PDF]
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K. F. Hoffmann, A. W. Cheever, and T. A. Wynn IL-10 and the Dangers of Immune Polarization: Excessive Type 1 and Type 2 Cytokine Responses Induce Distinct Forms of Lethal Immunopathology in Murine Schistosomiasis J. Immunol., June 15, 2000; 164(12): 6406 - 6416. [Abstract] [Full Text] [PDF]
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I. O. Farah, P. W. Mola, T. M. Kariuki, M. Nyindo, R. E. Blanton, and C. L. King Repeated Exposure Induces Periportal Fibrosis in Schistosoma mansoni-Infected Baboons: Role of TGF-{beta} and IL-4 J. Immunol., May 15, 2000; 164(10): 5337 - 5343. [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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 J. Koglin, T. Glysing-Jensen, S. Gadiraju, and M. E. Russell Attenuated Cardiac Allograft Vasculopathy in Mice With Targeted Deletion of the Transcription Factor STAT4 Circulation, March 7, 2000; 101(9): 1034 - 1039. [Abstract] [Full Text] [PDF]
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P. G. Fallon, E. J. Richardson, G. J. McKenzie, and A. N. J. McKenzie Schistosome Infection of Transgenic Mice Defines Distinct and Contrasting Pathogenic Roles for IL-4 and IL-13: IL-13 Is a Profibrotic Agent J. Immunol., March 1, 2000; 164(5): 2585 - 2591. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, M. Hesse, A. W. Cheever, and T. A. Wynn CpG Oligonucleotides Can Prophylactically Immunize Against Th2-Mediated Schistosome Egg-Induced Pathology by an IL-12-Independent Mechanism J. Immunol., January 15, 2000; 164(2): 973 - 985. [Abstract] [Full Text] [PDF]
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M. H. Kaplan, A. L. Wurster, S. T. Smiley, and M. J. Grusby3 Stat6-Dependent and -Independent Pathways for IL-4 Production J. Immunol., December 15, 1999; 163(12): 6536 - 6540. [Abstract] [Full Text] [PDF]
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Y. Chen and D. L. Boros Polarization of the Immune Response to the Single Immunodominant Epitope of p38, a Major Schistosoma mansoni Egg Antigen, Generates Th1- or Th2-Type Cytokines and Granulomas Infect. Immun., September 1, 1999; 67(9): 4570 - 4577. [Abstract] [Full Text] [PDF]
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M. A. Montesano, D. G. Colley, G. L. Freeman Jr., and W. E. Secor Neonatal Exposure to Idiotype Induces Schistosoma mansoni Egg Antigen-Specific Cellular and Humoral Immune Responses J. Immunol., July 15, 1999; 163(2): 898 - 905. [Abstract] [Full Text] [PDF]
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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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G. J. McKenzie, P. G. Fallon, C. L. Emson, R. K. Grencis, and A. N.J. McKenzie Simultaneous Disruption of Interleukin (IL)-4 and IL-13 Defines Individual Roles in T Helper Cell Type 2-mediated Responses J. Exp. Med., May 17, 1999; 189(10): 1565 - 1572. [Abstract] [Full Text] [PDF]
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A. W. Cheever, R. W. Poindexter, and T. A. Wynn Egg Laying Is Delayed but Worm Fecundity Is Normal in SCID Mice Infected with Schistosoma japonicum and S. mansoni with or without Recombinant Tumor Necrosis Factor Alpha Treatment Infect. Immun., May 1, 1999; 67(5): 2201 - 2208. [Abstract] [Full Text] [PDF]
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M. Lohning, J. L. Grogan, A. J. Coyle, M. Yazdanbakhsh, C. Meisel, J.-C. Gutierrez-Ramos, A. Radbruch, and T. Kamradt T1/ST2 Expression Is Enhanced on CD4+ T Cells from Schistosome Egg-Induced Granulomas: Analysis of Th Cell Cytokine Coexpression Ex Vivo J. Immunol., April 1, 1999; 162(7): 3882 - 3889. [Abstract] [Full Text] [PDF]
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P. G. Fallon and D. W. Dunne Tolerization of Mice to Schistosoma mansoni Egg Antigens Causes Elevated Type 1 and Diminished Type 2 Cytokine Responses and Increased Mortality in Acute Infection J. Immunol., April 1, 1999; 162(7): 4122 - 4132. [Abstract] [Full Text] [PDF]
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D. L. Boros and J. R. Whitfield Enhanced Th1 and Dampened Th2 Responses Synergize To Inhibit Acute Granulomatous and Fibrotic Responses in Murine Schistosomiasis Mansoni Infect. Immun., March 1, 1999; 67(3): 1187 - 1193. [Abstract] [Full Text] [PDF]
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L. M. Stamm, A. Raisanen-Sokolowski, M. Okano, M. E. Russell, J. R. David, and A. R. Satoskar Mice with STAT6-Targeted Gene Disruption Develop a Th1 Response and Control Cutaneous Leishmaniasis J. Immunol., December 1, 1998; 161(11): 6180 - 6188. [Abstract] [Full Text] [PDF]
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A. L. Dent, J. Hu-Li, W. E. Paul, and L. M. Staudt T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6 PNAS, November 10, 1998; 95(23): 13823 - 13828. [Abstract] [Full Text] [PDF]
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K. F. Hoffmann, P. Caspar, A. W. Cheever, and T. A. Wynn IFN-{gamma}, IL-12, and TNF-{alpha} Are Required to Maintain Reduced Liver Pathology in Mice Vaccinated with Schistosoma mansoni Eggs and IL-12 J. Immunol., October 15, 1998; 161(8): 4201 - 4210. [Abstract] [Full Text] [PDF]
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L. I. Rutitzky, H. J. Hernandez, and M. J. Stadecker Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection PNAS, November 6, 2001; 98(23): 13243 - 13248. [Abstract] [Full Text] [PDF]
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