title: Targeting tumour necrosis factor receptor 1 assembly reverses Th17-mediated colitis through boosting a Th2 response.
abstract: OBJECTIVE
  The soluble preligand assembly domain (PLAD) of tumour necrosis factor receptor 1 (TNFR1) interferes with receptor trimerisation to block downstream signalling, and mediates Th17 suppression. We explored the therapeutic potential of recombinant PLAD.Fc protein on a spontaneous experimental colitis.
  
  
  METHODS
  A T-cell-specific BLIMP-1 knockout mouse model with mixed Th1/Th17 responses, resembling human Crohn's disease (CD) was established, and its colitogenic phenotype was characterised. Mice, 9 weeks old, were treated with PLAD.Fc protein at 5 mg/kg of body weight twice per week for 16 weeks, and presence of colitis was monitored by the appearance of diarrhoea, weight loss, and by histological colonic scoring. Activation status, cytokine profiles, and transcription factors in T cells were further analysed.
  
  
  RESULTS
  The colitogenic phenotype in BLIMP-1 knockout mice was alleviated when an interleukin (IL)-23 knockdown transgene was introduced, indicating a therapeutic potential by downregulating IL-23-Th17 axis in these knockout mice. In PLAD.Fc-treated group, the mouse body weight remained stable and only mild disease scores were revealed. The percentage of naive CD4 T cells was increased and that of effector/memory CD4 T cells was decreased after PLAD.Fc-treatment. Moreover, the levels of IFN-γ, IL-17, IL-21, IL-22, IL-23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α were diminished. Strikingly, Th2-associated cytokines (IL-4, IL-13 and IL-10) in sera, as well as percentages of Th2 cells, were increased in PLAD.Fc-treated mice. However, PLAD.Fc-mediated suppression of effector phenotypes in Th1/Th17 was abrogated after neutralising IL-10.
  
  
  CONCLUSIONS
  The Th2 cytokine milieu induced by PLAD.Fc rebalanced T-helper cell subsets and conferred a protection against colitis in BLIMP-1 knockout mice.
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shin-Huei
authors.initials: SH
authors.lastname: Fu
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Lin
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Li-Tzu
authors.initials: LT
authors.lastname: Yeh
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan Research Center for Composite Tissue Allotransplantation, Chang-Gung Memorial Hospital, Tao-Yuan Hsien, Taiwan.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Chien
authors.affiliation: Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017353:Gene Deletion; D053759:Interleukin-23 / Q000276:immunology; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics
chemical_list: D053759:Interleukin-23; C000598437:PLAD.Fc fusion protein; C513258:Prdm1 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: AUTOIMMUNE DISEASE; CROHN'S DISEASE; IBD BASIC RESEARCH; T LYMPHOCYTES; TNF-ALPHA