Objective. Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.Methods. One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.Results. The dnaJP1 peptide was safe and welltolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor ␣ and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. AnalyClinicalTrials.gov identifier: NCT00000435.

Progress in our understanding of the genetics and immunology of rheumatoid arthritis (RA) has translated into clinical practice with the introduction of a first generation of biologic agents that effectively interfere with the inflammatory cascade by blocking a key component. This evolution has not only changed the way we practice, but perhaps also the way we think about RA and its treatment. In our view direct manipulation of specific pathogenic pathways is increasingly being used to replace generalized pharmacological immune suppression. The next leap forward will be to develop therapeutic approaches that will lead to maintenance of disease remission with a minimal-treatment or even drug-free regimen, relying on the induction of immune tolerance rather than the suppression of the immune system. Immune tolerance has the potential to prevent tissue damage secondary to inflammatory responses while at the same time maintaining homeostasis through physiologic recognition of self and the ability to perceive and react to 'danger'. Novel therapeutic approaches are emerging from these concepts. Such therapies will hopefully be safe and efficacious, and will complement the first generation of biologic agents that are currently available.

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation.