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TNFα kinoid vaccination-induced neutralizing antibodies to TNFα protect mice from autologous TNFα-driven chronic and acute inflammation

Le Buanec, Hélène, Delavallée, Laure, Bessis, Natacha, Paturance, Sébastien, Bizzini, Bernard, Gallo, Robert, Zagury, Daniel, Boissier, Marie-Christophe
Proceedings of the National Academy of Sciences of the United States of America 2006 v.103 no.51 pp. 19442-19447
Crohn disease, adjuvants, antigens, bioactive properties, genetically modified organisms, humans, immune response, inflammation, mice, models, neutralization, neutralizing antibodies, rheumatoid arthritis, septic shock, synovitis, tumor necrosis factor-alpha, vaccination, vaccines
The proinflammatory cytokine TNFα is a potent mediator of septic shock and a therapeutic target for chronic inflammatory pathologies including rheumatoid arthritis and Crohn's disease. As an alternative to anti-human TNFα (hTNFα) mAbs and other hTNFα blocker approved drugs, we developed an active anti-hTNFα immunotherapy, based on a vaccine comprised of a keyhole limpet hemocyanin-hTNFα heterocomplex immunogen (hTNFα kinoid) adjuvanted in incomplete Freund's adjuvant. In mice transgenic for hTNFα (TTg mice), hTNFα kinoid vaccination elicited high titers of Abs that neutralized hTNFα bioactivities but did not result in a cellular response to hTNFα. The vaccine was safe and effective in two experimental models. Kinoid-immunized but not control TTg mice resisted hTNFα-driven shock in one model and were prevented from spontaneous arthritis, inflammatory synovitis, and articular destruction in a second model. These data demonstrate an anti-cytokine induction of autoimmune protection against both acute and chronic hTNFα exposure. They show that active vaccination against a human cytokine can be achieved, and that the immune response can be effective and safe.