Epitope‐specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double‐blind, placebo‐controlled, pilot phase II trial

Abstract

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.

APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients

“…Tregs need to be activated via their T cell receptor for maintaining their suppressive potential; this implicates that their cognate antigen should be abundantly present and presented in the context of MHC class II molecules in the inflamed joints. We and others believe that peptides derived from HSPs could be such antigens (Prakken et al 2004;van Eden et al 2005;Koffeman et al 2009;Zonneveld-Huijssoon et al 2013;Barberá et al 2015). HSP60-peptides are considered bystander antigens because they are upregulated at the site of inflammation and are immunologically dominant.…”

Tolerization against atherosclerosis using heat shock protein 60

“…Thus, even if the tolerizing approach in mice may form the basis for the subsequent development of such a vaccine in humans, it is rather improbable that the same HSP60 peptide candidate will emerge as atherogenic in both species. However, promising results from clinical trials for treating rheumatoid arthritis and type I diabetes are currently ongoing (Prakken et al 2004;Raz et al 2001Raz et al , 2007Huurman et al 2007Huurman et al , 2008Lazar et al 2007;Koffeman et al 2009). A better understanding of these networks is highly warranted.…”

T cell recognition of naturally presented epitopes of self-heat shock protein 70

“…T cell reactivity toward HSP70 epitopes is not yet described in human autoimmune diseases. Nevertheless, T cell response toward other self-heat shock protein peptides (DiaPep277, pan-DR binding HSP60, DnaJp1) is present in autoimmune diseases such as in type I diabetes (Huurman et al 2008;Raz et al 2001), juvenile idiopathic arthritis, and rheumatoid arthritis (de Jong et al 2009;Kamphuis et al 2005;Koffeman et al 2009;Prakken et al 2004). Knowledge of T cell responses toward these self-epitopes in chronic inflammation could help find strategies to restore the immune balance in chronic inflammation.…”