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

The proinflammatory cytokine TNF alpha 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 TNF alpha (hTNF alpha) mAbs and other hTNF alpha blocker approved drugs, we developed an active anti-hTNF alpha immunotherapy, based on a vaccine comprised of a keyhole limpet hemocyanin-hTNF alpha heterocomplex immunogen (hTNF alpha kinoid) adjuvanted in incomplete Freund's adjuvant. In mice transgenic for hTNF alpha (TTg mice), hTNF alpha kinoid vaccination elicited high titers of Abs that neutralized hTNF alpha bioactivities but did not result in a cellular response to hTNF alpha. The vaccine was safe and effective in two experimental models. Kinoid-immunized but not control TTg mice resisted hTNF alpha-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 hTNF alpha exposure. They show that active vaccination against a human cytokine can be achieved, and that the immune response can be effective and safe.