Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis.
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-gamma, and tumor necrosis factor-alpha 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.
Prakken
Berent J
BJ
Departments of Medicine and Pediatrics, and IACOPO Institute for Translational Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, USA.
Samodal
Rodrigo
R
Le
Tho D
TD
Giannoni
Francesca
F
Yung
Gisella Puga
GP
Scavulli
John
J
Amox
Diane
D
Roord
Sarah
S
de Kleer
Isme
I
Bonnin
Dustan
D
Lanza
Paola
P
Berry
Charles
C
Massa
Margherita
M
Billetta
Rosario
R
Albani
Salvatore
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000187:drug effects; D000939:Epitopes / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects / Q000276:immunology; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D000939:Epitopes; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; D015375:Receptors, Interleukin-2