Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis

Abstract

Modulation of epitope-specific immune responses would represent a major addition to available therapeutic options for many autoimmune diseases. The objective of this work was to induce immune deviation by mucosal peptide-specific immunotherapy in rheumatoid arthritis (RA) patients, and to dissect the related immunological mechanisms by using a technology for the detection of low-affinity class II-restricted peptide-specific T cells. A group of patients with early RA was treated for 6 months orally with dnaJP1, a peptide that induces proinflammatory T cell responses in naive RA patients. Immunological analysis at initial, intermediate and end treatment points showed an intriguing change from proinflammatory to regulatory T cell function. In fact, dnaJP1-induced T cell production of IL-4 and IL-10 increased significantly when initial and end treatment points were compared, whereas dnaJP1-induced T cell proliferation and production of IL-2, IFN-␥, and tumor necrosis factor-␣ decreased significantly. The total number of dnaJP1-specific cells did not change over time, whereas expression of foxP3 by CD4 ؉ CD25 bright cells increased, suggesting that the treatment affected regulatory T cell function. Thus, rather than clonal deletion, the observed change in immune reactivity to dnaJP1 was the outcome of treatment-induced emergence of T cells with a different functional phenotype. This study contributes to our knowledge of mechanisms and tools needed for antigen-specific immune modulation in humans, thus laying the foundation for exploitation of this approach for therapeutic purposes.

PAN–DR‐Binding Hsp60 self epitopes induce an interleukin‐10–mediated immune response in rheumatoid arthritis

“…Recently, phase I and phase II immunotherapy trials with epitopes derived from DnaJ HSP and Hsp60 showed great promise in RA (refs. 23 and 43 and Koffeman E, et al: unpublished observations) and type II diabetes mellitus (23,44), respectively. Over the years, a large amount of data has been gathered, in experimental arthritis models as well as in patients with JIA and patients with RA, suggesting that Hsp60 is a potential target for immunotherapy in arthritis (24).…”

“…We previously showed that DnaJ P1, a peptide derived from another HSP, induces proinflammatory responses in PBMCs from patients with early RA and can be used to modulate autoimmune inflammation in these patients (23). The results from the present study show that the phenomenon of disease-and inflammation-specific recognition of HSP-derived epitopic peptides, which we first described in patients with RA using DnaJ P1, is, in reality, more complex and involves peptides that are functionally similar to DnaJ P1 (proinflammatory) as well as others that are quite different (50).…”

“…They are expressed during inflammatory conditions and are dominantly recognized by the immune system, thus fulfilling important criteria for candidate antigens for immune therapy. Indeed, a peptide derived from the DnaJ HSP has shown promise in a phase I study in patients with RA, with a phase II trial currently being performed (22,23). For the present study, we focused on another HSP, namely, Hsp60.…”

Distinct gene signature revealed in white blood cells, CD4+ and CD8+ T cells in (NZBx NZW) F1 lupus mice after tolerization with anti-DNA Ig peptide

“…[1][2][3][4][5][6][7] Studies on human autoimmune diseases including SLE have reported amelioration of inflammatory responses and increases in CD4 þ CD25 þ Treg cells following treatment with self-antigen-derived peptides. [8][9][10][11][12][13][14][15][16] Similarly, self-antigen-derived peptides have also been used to induce immune tolerance and ameliorate disease in murine lupus models. 15,[17][18][19][20][21][22][23][24][25] Our group has developed a novel peptide pConsensus (pCons) that is based on MHC Class I and Class II T-cell determinants in the heavy chain region of murine anti-DNA IgG.…”

Heat-shock proteins induce T-cell regulation of chronic inflammation

“…HSP immunisations have been shown to inhibit autoimmune disorders such as diabetes and arthritis both in animal models and in initial clinical trials in patients with chronic inflammatory disease. [5][6][7][8][9][10][11][12] Over the past years, several research groups have shown that HSP reactive T cells might play a role in this regulatory function and in the induction of anti-inflammatory cytokines in chronic inflammation.…”