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

Eva C. Koffeman, Mark Genovese, Diane Amox, Elissa Keogh, Ernesto Santana, Eric Lawrence Matteson, Arthur Kavanaugh, Jerry A. Molitor, Michael H. Schiff, James O. Posever, Joan M. Bathon, Alan J. Kivitz, Rodrigo Samodal, Francis Belardi, Carolyn Dennehey, Theo Van Den Broek, Femke Van Wijk, Xiao Zhang, Peter Zieseniss, Tho LeBerent A. Prakken, Gary C. Cutter, Salvatore Albani

Research output: Contribution to journalArticle

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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 α 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. Analy-sis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. Conclusion. Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.

Original languageEnglish (US)
Pages (from-to)3207-3216
Number of pages10
JournalArthritis and Rheumatism
Volume60
Issue number11
DOIs
StatePublished - Nov 2009

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Immunotherapy
Epitopes
Rheumatoid Arthritis
Placebos
Hydroxychloroquine
T-Lymphocytes
Immune Tolerance
Phenotype
Peptides
Adaptive Immunity
Therapeutics
Interleukin-10
Down-Regulation
Tumor Necrosis Factor-alpha
Ligands
Inflammation
Research
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

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. / Koffeman, Eva C.; Genovese, Mark; Amox, Diane; Keogh, Elissa; Santana, Ernesto; Matteson, Eric Lawrence; Kavanaugh, Arthur; Molitor, Jerry A.; Schiff, Michael H.; Posever, James O.; Bathon, Joan M.; Kivitz, Alan J.; Samodal, Rodrigo; Belardi, Francis; Dennehey, Carolyn; Van Den Broek, Theo; Van Wijk, Femke; Zhang, Xiao; Zieseniss, Peter; Le, Tho; Prakken, Berent A.; Cutter, Gary C.; Albani, Salvatore.

In: Arthritis and Rheumatism, Vol. 60, No. 11, 11.2009, p. 3207-3216.

Research output: Contribution to journalArticle

Koffeman, EC, Genovese, M, Amox, D, Keogh, E, Santana, E, Matteson, EL, Kavanaugh, A, Molitor, JA, Schiff, MH, Posever, JO, Bathon, JM, Kivitz, AJ, Samodal, R, Belardi, F, Dennehey, C, Van Den Broek, T, Van Wijk, F, Zhang, X, Zieseniss, P, Le, T, Prakken, BA, Cutter, GC & Albani, S 2009, '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', Arthritis and Rheumatism, vol. 60, no. 11, pp. 3207-3216. https://doi.org/10.1002/art.24916
Koffeman, Eva C. ; Genovese, Mark ; Amox, Diane ; Keogh, Elissa ; Santana, Ernesto ; Matteson, Eric Lawrence ; Kavanaugh, Arthur ; Molitor, Jerry A. ; Schiff, Michael H. ; Posever, James O. ; Bathon, Joan M. ; Kivitz, Alan J. ; Samodal, Rodrigo ; Belardi, Francis ; Dennehey, Carolyn ; Van Den Broek, Theo ; Van Wijk, Femke ; Zhang, Xiao ; Zieseniss, Peter ; Le, Tho ; Prakken, Berent A. ; Cutter, Gary C. ; Albani, Salvatore. / 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. In: Arthritis and Rheumatism. 2009 ; Vol. 60, No. 11. pp. 3207-3216.
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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 α 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. Analy-sis of the primary efficacy end point (meeting the American College of Rheumatology 20{\%} improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. Conclusion. Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.",
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T2 - 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

AU - Koffeman, Eva C.

AU - Genovese, Mark

AU - Amox, Diane

AU - Keogh, Elissa

AU - Santana, Ernesto

AU - Matteson, Eric Lawrence

AU - Kavanaugh, Arthur

AU - Molitor, Jerry A.

AU - Schiff, Michael H.

AU - Posever, James O.

AU - Bathon, Joan M.

AU - Kivitz, Alan J.

AU - Samodal, Rodrigo

AU - Belardi, Francis

AU - Dennehey, Carolyn

AU - Van Den Broek, Theo

AU - Van Wijk, Femke

AU - Zhang, Xiao

AU - Zieseniss, Peter

AU - Le, Tho

AU - Prakken, Berent A.

AU - Cutter, Gary C.

AU - Albani, Salvatore

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