title: Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice.
abstract: OBJECTIVE
  Interleukin (IL)-23 supports a distinct lineage of T cells producing IL-17 (Th17) that can mediate chronic inflammation. This study was performed to define the role of IL-23 and Th17 cells in chronic colitis in mice.
  
  
  METHODS
  Colitis was induced by transfer of a cecal bacterial antigen-specific C3H/HeJBir (C3Bir) CD4(+) T-cell line to C3H/HeSnJ SCID mice. Cytokines were measured by flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Monoclonal anti-IL-23p19 was administered at the same time as or 4 weeks after pathogenic CD4 T-cell transfer. A histopathology colitis score was assessed in a blinded fashion.
  
  
  RESULTS
  The pathogenic C3Bir CD4(+) T-cell line contained more cells producing IL-17 than those producing interferon-gamma and these were distinct subsets; after adoptive transfer to SCID recipients, Th17 cells were predominant in the lamina propria of mice with colitis. Bacteria-reactive CD4(+) Th1 and Th17 lines were generated. The Th17 cells induced marked inflammation in a dose-dependent manner. Even at a dose as low as 10(4) cells/mouse, Th17 cells induced more severe disease than Th1 cells did at 10(6) cells/mouse. Monoclonal anti-IL-23p19 prevented and treated active colitis, with down-regulation of a broad array of inflammatory cytokines and chemokines in the colon. Anti-IL-23p19 induced apoptosis in colitogenic Th17 cells in vitro and in vivo.
  
  
  CONCLUSIONS
  Bacterial-reactive CD4(+) Th17 cells are potent effector cells in chronic colitis. Inhibition of IL-23p19 was effective in both prevention and treatment of active colitis. IL-23 is an attractive therapeutic target for inflammatory bowel disease.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA. coelson@uab.edu
authors.forename: Charles O
authors.initials: CO
authors.lastname: Elson
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: Terrill K
authors.initials: TK
authors.lastname: McClanahan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Fick
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kastelein
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002432:Cecum / Q000382:microbiology; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D016176:T-Lymphocyte Subsets / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D018664:Interleukin-12; D007371:Interferon-gamma