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Active immunisation targeting soluble murine tumour necrosis factor alpha is safe and effective in collagen-induced arthritis model treatment
J.H. Sun1, Y.H. Zhang2, J.Y. Kuang3, G. Liu4, Y.X. Liu5, B.H. Liu6
- Department of Rheumatology, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
- Department of Rheumatology, People’s Hospital of BoZho, AnHui Province, China.
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Department of Rheumatology, West China Medical School, Sichuan University, Chengdu, Sichuan, China. neoliugang@163.com
- Department of Clinical Medicine, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
- Department of Rheumatology, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
CER8542
2016 Vol.34, N°2
PI 0242, PF 0246
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PMID: 26811933 [PubMed]
Received: 19/04/2015
Accepted : 12/10/2015
In Press: 20/01/2016
Published: 13/04/2016
Abstract
OBJECTIVES:
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 TNFα4-23 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.
