title: Active immunisation targeting soluble murine tumour necrosis factor alpha is safe and effective in collagen-induced arthritis model treatment.
abstract: OBJECTIVE
  TNF-α has been proved to be an effective target in rheumatoid arthritis treatment. So far, all the commercialised TNF-α antagonists function as passive immunotherapy. The aim of this study was to design a complex which can trigger active immunisation and overcome self-tolerance to elicit antibodies against murine TNF-α.
  
  
  METHODS
  The complex (KLH-TNF) was chemically synthesised by linking a selected peptide TNFα(4-23) from murine soluble TNF-α to a carrier protein, keyhole limpet haemocyanin (KLH). We evaluated its safety and antibody eliciting performance. We also evaluated its disease-regulating ability on collagen-induced arthritis models. Furthermore, the immune cells responses were analysed by T cell proliferation assay and B cell memory experiments.
  
  
  RESULTS
  The complex was safe without cytotoxity. The anti-mTNF-α antibody titers of the KLH-TNF group were 400 times greater than the control groups (p<0.0001). The elicited antibodies could combine with soluble TNF-α. The antibody response was independent of autologous TNF-α and could be reinforced by booster immunisation. Moreover, the complex did not trigger T cell activation and B cell memory response against native TNF-α. In animal experiments, KLH-TNF immunized mice showed a lower arthritis score (p<0.001) and better weight gain (p<0.01). Histological evaluations showed milder inflammation and cartilage depletion.
  
  
  CONCLUSIONS
  Active immunotherapy against cytokine TNF-α is feasible by conjugating cytokine peptide with carrier protein. The elicited antibodies could combine with the native TNF-α and inhibit its activity. Importantly, the antibody response is reversible and independent of autologous TNF-α.
authors.affiliation: Department of Rheumatology, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jian Hong
authors.initials: JH
authors.lastname: Sun
authors.affiliation: Department of Rheumatology, People's Hospital of BoZho, AnHui Province, China.
authors.forename: Yu Hui
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Jiang Ying
authors.initials: JY
authors.lastname: Kuang
authors.affiliation: Department of Rheumatology, West China Medical School, Sichuan University, Chengdu, Sichuan, China. neoliugang@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Clinical Medicine, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Yi Xin
authors.initials: YX
authors.lastname: Liu
authors.affiliation: Department of Rheumatology, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Bin Han
authors.initials: BH
authors.lastname: Liu
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014611:Vaccination
chemical_list: D014409:Tumor Necrosis Factor-alpha