Abstract
IntroductionPassive blockade of tumor necrosis factor-alpha (TNF-α) has demonstrated high therapeutic efficiency in chronic inflammatory diseases, such as rheumatoid arthritis, 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.MethodshTNF-α transgenic mice, which spontaneously develop arthritides from 8 weeks of age, were immunized with a heterocomplex (TNF kinoid, or TNF-K) composed of hTNF-α and keyhole limpet hemocyanin after disease onset. We evaluated arthritides by clinical and histological assessment, and titers of neutralizing anti-hTNF-α antibody by enzyme-linked immunosorbent assay and L929 assay.ResultsArthritides 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.ConclusionsAnti-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.
Highlights
Passive blockade of tumor necrosis factor-alpha (TNF-α) has demonstrated high therapeutic efficiency in chronic inflammatory diseases, such as rheumatoid arthritis, some concerns remain such as occurrence of resistance and high cost
It has been demonstrated that TNF-α mediates a wide variety of effector functions in Rheumatoid arthritis (RA), including the release of pro-inflammatory cytokines and chemokines, leukocyte accumulation, angiogenesis, and the ANOVA: analysis of variance; confidence intervals (CIs): confidence interval; enzymelinked immunosorbent assay (ELISA): enzyme-linked immunosorbent assay; human TNF-α (hTNF-α): human tumor necrosis factor-alpha; IL: interleukin; IM: intramuscular; IP: intraperitoneal; KLH: keyhole limpet hemocyanin; monoclonal antibodies (mAbs): monoclonal antibody; OD: optical density; phosphate-buffered saline (PBS): phosphatebuffered saline; RA: rheumatoid arthritis; TNF-α: tumor necrosis factor-alpha; TNF-K: tumor necrosis factor kinoid; TNF-K in hTNF-α transgenic (TTg): human tumor necrosis factoralpha transgenic
The native hTNF-α doses were chosen based on previous results we obtained in a TNF-α-dependent lethal shock experiment, in which we showed that 1 μg of native hTNF-α injections in TTg mice sensibilized with D-galactosamine was enough to kill the mice [12]
Summary
Passive blockade of tumor necrosis factor-alpha (TNF-α) has demonstrated high therapeutic efficiency in chronic inflammatory diseases, such as rheumatoid arthritis, some concerns remain such as occurrence of resistance and high cost. These limitations prompted investigations of an alternative strategy to target TNF-α. Based on the pivotal role of TNF-α in the pathogenesis of RA [4], two classes of biologic drugs to block this cytokine have been developed: a soluble TNF-α receptor (etanercept) and TNF-binding monoclonal antibodies (mAbs) such as infliximab, adalimumab, golimumab, or certolizumab [5,6] They show a rapid and substantial therapeutic benefit in most patients, with a good safety profile, primary unresponsiveness and secondary escape phenomena are not uncommon [7]. The tremendous success of TNF-α blockade by mAbs has sparked interest in developing alternative strategies for antagonizing TNF-α, such as gene therapy by electrotransfer [8], short interfering RNA [9], or active anti-TNF-α immunotherapy [10,11,12,13]
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