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.
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 well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha 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. Analysis 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.


CONCLUSIONS
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.
Koffeman
Eva C
EC
University of California, San Diego, La Jolla, CA, USA.
Genovese
Mark
M
Amox
Diane
D
Keogh
Elissa
E
Santana
Ernesto
E
Matteson
Eric L
EL
Kavanaugh
Arthur
A
Molitor
Jerry A
JA
Schiff
Michael H
MH
Posever
James O
JO
Bathon
Joan M
JM
Kivitz
Alan J
AJ
Samodal
Rodrigo
R
Belardi
Francis
F
Dennehey
Carolyn
C
van den Broek
Theo
T
van Wijk
Femke
F
Zhang
Xiao
X
Zieseniss
Peter
P
Le
Tho
T
Prakken
Berent A
BA
Cutter
Gary C
GC
Albani
Salvatore
S
D056704:Adaptive Immunity / Q000276:immunology; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D006886:Hydroxychloroquine / Q000627:therapeutic use; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D050956:HSP40 Heat-Shock Proteins; D016056:Immunodominant Epitopes; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D006886:Hydroxychloroquine