Anti-TNF alpha active immunization is effective in chronic established inflammatory disease: long term study in a TNFalpha transgenic model of arthritis

Background. . Passive blockade of Tumor Necrosis Factor α (TNF-α) has demonstrated high therapeutic efficacy in chronic inflammatory diseases, such as Rheumatoid Arthritis (RA), although some concerns remain such as occurrence of resistance and high cost. These limitations prompted investigations of an alternative strategy to target TNF-α. This study sought to demonstrate a long-lasting therapeutic effect on established arthritis of an active immunotherapy to human (h) TNF-α, and to evaluate the long-term consequences of an endogenous anti-TNF-α response. Methods. hTNF-α transgenic (TTg) mice, which spontaneously develop arthritis from 8 weeks of age, were immunized with a heterocomplex (TNF-K) composed of hTNF-α and Keyhole Limpet Hemocyanin (KLH), after the disease onset. We evaluated arthritides by clinical and histological assessment, and titers of neutralizing anti-hTNFα antibody by ELISA and L929 assay. Results. Arthritides were dramatically improved compared to control mice at week 27. TNF-K treated mice exhibited high levels of neutralizing anti-hTNF-α antibodies. Between weeks 27 and 45, all immunized mice exhibited symptoms of clinical deterioration, and a parallel decrease in anti-hTNF-α neutralizing antibodies. A maintenance dose of TNF-K reversed the clinical deterioration and increased the anti-hTNF-α antibody titer. At 45 weeks TNF-K long-term efficacy was confirmed by low clinical and mild histological scores for the TNF-K treated mice. Injections of unmodified hTNF-α did not induce a recall response to hTNF-α in TNF-K immunized mice. Conclusions. Anti-TNF-α immunotherapy with TNF-K has a sustained but reversible therapeutic efficacy in an established disease model, supporting the potential suitability of this approach in treating human disease.