title: Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4+ T-cell responses in murine colitis.
abstract: BACKGROUND
  The efficacy of anti-tumor necrosis factor monoclonal antibody (anti-TNF mAb) for Crohn's disease (CD) is well established, and anti-interleukin-6 receptor (anti-IL-6R) mAb has also been reported to be effective in CD. It is, however, unclear if the efficacy and mechanisms of both agents are different in CD therapy.
  
  
  METHODS
  Using an adoptive transfer colitis model, we compared the efficacy of anti-IL-6R mAb, anti-TNF mAb, and TNF receptor-Fc fusion protein (TNFR-Fc), and their modes of action on CD4+ T cells. We also investigated the role of Th1 and Th17 cells in colitis using the same model.
  
  
  RESULTS
  The histological scores for the anti-IL-6R mAb and anti-TNF mAb groups but not for TNFR-Fc group were much lower than that for the control group, and the score was the lowest for the anti-IL-6R mAb group. The frequency of proliferating CD4+ T cells was reduced in anti-IL-6R mAb and anti-TNF mAb groups, but not in the TNFR-Fc group, whereas the frequency of apoptotic CD4+ T cells was similar in all groups. Anti-IL-6R mAb suppressed the induction of Th17 cells and increased the frequency of lamina propria regulatory T cells, whereas anti-TNF mAb exerted no influence on CD4+ T-cell differentiation. A deficiency in interferon-γ and/or IL-17 in CD4+ T cells reduced the severity of colitis.
  
  
  CONCLUSIONS
  Our findings suggest that suppression of the proliferation of pathogenic CD4+ T cells is the major mode of action of biological agents for colitis therapy. Anti-IL-6R mAb might have benefits in CD patients with Th17 dominance and impaired Treg frequency.
authors.affiliation: Laboratory for Immune Signal, National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Terabe
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shinzaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kawahata
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ohsugi
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma