title: A Rationally Designed TNF-α Epitope-Scaffold Immunogen Induces Sustained Antibody Response and Alleviates Collagen-Induced Arthritis in Mice.
abstract: The TNF-α biological inhibitors have significantly improved the clinical outcomes of many autoimmune diseases, in particular rheumatoid arthritis. However, the practical uses are limited due to high costs and the risk of anti-drug antibody responses. Attempts to develop anti-TNF-α vaccines have generated encouraging data in animal models, however, data from clinical trials have not met expectations. In present study, we designed a TNF-α epitope-scaffold immunogen DTNF7 using the transmembrane domain of diphtheria toxin, named DTT as a scaffold. Molecular dynamics simulation shows that the grafted TNF-α epitope is entirely surface-exposed and presented in a native-like conformation while the rigid helical structure of DTT is minimally perturbed, thereby rendering the immunogen highly stable. Immunization of mice with alum formulated DTNF7 induced humoral responses against native TNF-α, and the antibody titer was sustained for more than 6 months, which supports a role of the universal CD4 T cell epitopes of DTT in breaking self-immune tolerance. In a mouse model of rheumatoid arthritis, DTNF7-alum vaccination markedly delayed the onset of collagen-induced arthritis, and reduced incidence as well as clinical score. DTT is presumed safe as an epitope carrier because a catalytic inactive mutant of diphtheria toxin, CRM197 has good clinical safety records as an active vaccine component. Taken all together, we show that DTT-based epitope vaccine is a promising strategy for prevention and treatment of autoimmune diseases.
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Medical Science, Department of Pharmacology and Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Aizhang
authors.initials: A
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Conghao
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Traditional Chinese Medicine, Nanjing, 210028, Jiangsu, China.
authors.forename: Wuguang
authors.initials: W
authors.lastname: Lu
authors.affiliation: Shanghai HyCharm Inc., 1 Fute Street East, Bldg. 458, Rm. 518, Shanghai 200131, China.
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.|Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education; Shanghai 200240, China.
authors.forename: Rongxiu
authors.initials: R
authors.lastname: Li