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,
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Gene Therapy Program,
Department of Medicine,
Department of Pediatrics,
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Department of Pathology, and
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Department of Physiology, Louisiana State University Medical Center, New Orleans, LA 70112;
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Bone Marrow Transplant Program, Tulane University, New Orleans, LA;
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Pennington Research Center, Baton Rouge, LA; and
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Immunex Corporation, Seattle, WA 98101
IL-17 is a novel cytokine secreted principally by CD4+ T cells. It has been shown to support the growth of hemopoietic progenitors in vitro; however, its in vivo effects are presently unknown. Adenovirus-mediated gene transfer of the murine IL-17 cDNA targeted to the liver (5 x 109 plaque-forming units (PFU) intravenous) resulted in a transiently transgenic phenotype, with dramatic effects on in vivo granulopoiesis. Initially, there was a significant increase (fivefold) in the peripheral white blood count (WBC), including a 10-fold rise in the absolute neutrophil count. This was associated with a doubling in the spleen size over 7–14 days after gene transfer, which returned to near baseline by day 21, although the white blood cell count remained elevated. There was a profound stimulation of splenic hemopoiesis as demonstrated by an increase in total cellularity by 50% 7 days after gene transfer and an increase in hemopoietic colony formation. A maximal increase in frequency of high proliferative potential colonies (HPPC) (11-fold) and CFU-granulocyte-macrophage (GM) and CFU-granulocyte-erythrocyte-megakaryocyte-monocyte (GEMM) (CFU) (6-fold) was seen on day 3 after IL-17 gene transfer. Both CFU and HPPC remained significantly elevated in the spleen throughout day 21, but at reduced levels compared with day 3. Bone marrow CFU and HPPC were elevated on day 3 only by 75% and 25%, respectively, without changes in total cellularity. Thus, murine IL-17 is a cytokine that can stimulate granulopoiesis in vivo. Since IL-17 is principally produced by CD4+ T cells, this cytokine could have therapeutic implications in AIDS-related bone marrow failure and opportunistic infections.
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E. Lubberts, L. van den Bersselaar, B. Oppers-Walgreen, P. Schwarzenberger, C. J. J. Coenen-de Roo, J. K. Kolls, L. A. B. Joosten, and W. B. van den Berg IL-17 Promotes Bone Erosion in Murine Collagen-Induced Arthritis Through Loss of the Receptor Activator of NF-{kappa}B Ligand/Osteoprotegerin Balance J. Immunol., March 1, 2003; 170(5): 2655 - 2662. [Abstract] [Full Text] [PDF]
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S. Ferretti, O. Bonneau, G. R. Dubois, C. E. Jones, and A. Trifilieff IL-17, Produced by Lymphocytes and Neutrophils, Is Necessary for Lipopolysaccharide-Induced Airway Neutrophilia: IL-15 as a Possible Trigger J. Immunol., February 15, 2003; 170(4): 2106 - 2112. [Abstract] [Full Text] [PDF]
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P. W. Hellings, A. Kasran, Z. Liu, P. Vandekerckhove, A. Wuyts, L. Overbergh, C. Mathieu, and J. L. Ceuppens Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 42 - 50. [Abstract] [Full Text] [PDF]
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J. Maertzdorf, A. D. M. E. Osterhaus, and G. M. G. M. Verjans IL-17 Expression in Human Herpetic Stromal Keratitis: Modulatory Effects on Chemokine Production by Corneal Fibroblasts J. Immunol., November 15, 2002; 169(10): 5897 - 5903. [Abstract] [Full Text] [PDF]
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S. B. Forlow, E. J. White, K. L. Thomas, G. J. Bagby, P. L. Foley, and K. Ley T Cell Requirement for Development of Chronic Ulcerative Dermatitis in E- and P-Selectin-Deficient Mice J. Immunol., November 1, 2002; 169(9): 4797 - 4804. [Abstract] [Full Text] [PDF]
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M. R. Kim, R. Manoukian, R. Yeh, S. M. Silbiger, D. M. Danilenko, S. Scully, J. Sun, M. L. DeRose, M. Stolina, D. Chang, et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production Blood, September 18, 2002; 100(7): 2330 - 2340. [Abstract] [Full Text] [PDF]
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T. Starnes, H. E. Broxmeyer, M. J. Robertson, and R. Hromas Cutting Edge: IL-17D, a Novel Member of the IL-17 Family, Stimulates Cytokine Production and Inhibits Hemopoiesis J. Immunol., July 15, 2002; 169(2): 642 - 646. [Abstract] [Full Text] [PDF]
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S. D. Hurst, T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, et al. New IL-17 Family Members Promote Th1 or Th2 Responses in the Lung: In Vivo Function of the Novel Cytokine IL-25 J. Immunol., July 1, 2002; 169(1): 443 - 453. [Abstract] [Full Text] [PDF]
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S. Aggarwal and A. L. Gurney IL-17: prototype member of an emerging cytokine family J. Leukoc. Biol., January 1, 2002; 71(1): 1 - 8. [Abstract] [Full Text] [PDF]
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G. Pan, D. French, W. Mao, M. Maruoka, P. Risser, J. Lee, J. Foster, S. Aggarwal, K. Nicholes, S. Guillet, et al. Forced Expression of Murine IL-17E Induces Growth Retardation, Jaundice, a Th2-Biased Response, and Multiorgan Inflammation in Mice J. Immunol., December 1, 2001; 167(11): 6559 - 6567. [Abstract] [Full Text] [PDF]
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S. B. Forlow, J. R. Schurr, J. K. Kolls, G. J. Bagby, P. O. Schwarzenberger, and K. Ley Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule-deficient mice Blood, December 1, 2001; 98(12): 3309 - 3314. [Abstract] [Full Text] [PDF]
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P. Ye, P. B. Garvey, P. Zhang, S. Nelson, G. Bagby, W. R. Summer, P. Schwarzenberger, J. E. Shellito, and J. K. Kolls Interleukin-17 and Lung Host Defense against Klebsiella pneumoniae Infection Am. J. Respir. Cell Mol. Biol., September 1, 2001; 25(3): 335 - 340. [Abstract] [Full Text] [PDF]
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 P. Ye, F. H. Rodriguez, S. Kanaly, K. L. Stocking, J. Schurr, P. Schwarzenberger, P. Oliver, W. Huang, P. Zhang, J. Zhang, et al. Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense J. Exp. Med., August 20, 2001; 194(4): 519 - 528. [Abstract] [Full Text] [PDF]
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P. Schwarzenberger, W. Huang, P. Oliver, P. Byrne, V. La Russa, Z. Zhang, and J. K. Kolls IL-17 Mobilizes Peripheral Blood Stem Cells with Short- and Long-Term Repopulating Ability in Mice J. Immunol., August 15, 2001; 167(4): 2081 - 2086. [Abstract] [Full Text] [PDF]
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E. Lubberts, L. A. B. Joosten, B. Oppers, L. van den Bersselaar, C. J. J. Coenen-de Roo, J. K. Kolls, P. Schwarzenberger, F. A. J. van de Loo, and W. B. van den Berg IL-1-Independent Role of IL-17 in Synovial Inflammation and Joint Destruction During Collagen-Induced Arthritis J. Immunol., July 15, 2001; 167(2): 1004 - 1013. [Abstract] [Full Text] [PDF]
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C. Infante-Duarte, H. F. Horton, M. C. Byrne, and T. Kamradt Microbial Lipopeptides Induce the Production of IL-17 in Th Cells J. Immunol., December 1, 2000; 165(11): 6107 - 6115. [Abstract] [Full Text] [PDF]
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J. Witowski, K. Pawlaczyk, A. Breborowicz, A. Scheuren, M. Kuzlan-Pawlaczyk, J. Wisniewska, A. Polubinska, H. Friess, G. M. Gahl, U. Frei, et al. IL-17 Stimulates Intraperitoneal Neutrophil Infiltration Through the Release of GRO{alpha} Chemokine from Mesothelial Cells J. Immunol., November 15, 2000; 165(10): 5814 - 5821. [Abstract] [Full Text] [PDF]
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M. Ziolkowska, A. Koc, G. Luszczykiewicz, K. Ksiezopolska-Pietrzak, E. Klimczak, H. Chwalinska-Sadowska, and W. Maslinski High Levels of IL-17 in Rheumatoid Arthritis Patients: IL-15 Triggers In Vitro IL-17 Production Via Cyclosporin A-Sensitive Mechanism J. Immunol., March 1, 2000; 164(5): 2832 - 2838. [Abstract] [Full Text] [PDF]
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 E. Tartour, F. Fossiez, I. Joyeux, A. Galinha, A. Gey, E. Claret, X. Sastre-Garau, J. Couturier, V. Mosseri, V. Vives, et al. Interleukin 17, a T-cell-derived Cytokine, Promotes Tumorigenicity of Human Cervical Tumors in Nude Mice Cancer Res., August 1, 1999; 59(15): 3698 - 3704. [Abstract] [Full Text] [PDF]
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 Y. Shi, S. J. Ullrich, J. Zhang, K. Connolly, K. J. Grzegorzewski, M. C. Barber, W. Wang, K. Wathen, V. Hodge, C. L. Fisher, et al. A Novel Cytokine Receptor-Ligand Pair. IDENTIFICATION, MOLECULAR CHARACTERIZATION, AND IN VIVO IMMUNOMODULATORY ACTIVITY J. Biol. Chem., June 16, 2000; 275(25): 19167 - 19176. [Abstract] [Full Text] [PDF]
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