The proinflammatory cytokine TNF␣ 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␣ (hTNF␣) mAbs and other hTNF␣ blocker approved drugs, we developed an active anti-hTNF␣ immunotherapy, based on a vaccine comprised of a keyhole limpet hemocyanin-hTNF␣ heterocomplex immunogen (hTNF␣ kinoid) adjuvanted in incomplete Freund's adjuvant. In mice transgenic for hTNF␣ (TTg mice), hTNF␣ kinoid vaccination elicited high titers of Abs that neutralized hTNF␣ bioactivities but did not result in a cellular response to hTNF␣. The vaccine was safe and effective in two experimental models. Kinoid-immunized but not control TTg mice resisted hTNF␣-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␣ exposure. They show that active vaccination against a human cytokine can be achieved, and that the immune response can be effective and safe.anticytokine vaccination ͉ rheumatoid arthritis ͉ TNF␣ therapeutic vaccination ͉ TNF␣-dependent shock T he pathogenesis of severe chronic diseases, including rheumatic diseases, autoimmunity, and cachexia, depend at least in part on cytokine dysregulation within altered tissues (1). In particular, the proinflammatory TNF␣ cytokine was shown to be critically involved in the pathogenesis of rheumatoid arthritis (RA) and further its inhibition by anti-TNF␣ Abs controls the disease in experimental models (2, 3). These data prompted anti-human TNF␣ (hTNF␣) mAb therapy for RA in humans (4, 5). Efficacy in preventing RA of either mouse-human chimeric (infliximab; ref. 4) or fully human (adalimumab; ref. 5) mAbs was first demonstrated in the transgenic mouse model expressing hTNF␣. These mice mimic the clinical and histopathological progression of RA in humans (6, 7). Thereafter, clinical trials using infliximab (8, 9) and adalimumab (10) were successfully completed. Today, these approved therapeutic mAbs, as well as soluble hTNF␣ receptor derivative (etanercept) specifically targeting hTNF␣, are used in therapy of autoimmune diseases (11,12). About 1 million patients to date have been treated with these TNF␣ blockers with clinical efficacy in RA (1), Crohn's disease (13), and psoriasis (14). Potential side effects, however, include the risk of infection (sepsis or tuberculosis; ref. 15) and the occurrence of anti-DNA autoAbs (16) and possibly lymphoma (17). Furthermore, these therapeutic approaches are expensive and cumbersome. These limitations prompted investigations of alternative strategies, including active anti-TNF␣ immunization, targeting TNF␣ pathogenic effects (18)(19)(20). In this report, we show that a biologically inactive but immunogenic hTNF␣ derivative, constituted of a keyhole limpet hemocyanin (KLH)-hTNF␣ heterocomplex, called hTNF␣ kinoid (21), successf...
