Drs. Martin and Capini contributed equally to this work.
Antigen-specific suppression of established arthritis in mice by dendritic cells deficient in NF-κB
Article first published online: 28 JUN 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 7, pages 2255–2266, July 2007
How to Cite
Martin, E., Capini, C., Duggan, E., Lutzky, V. P., Stumbles, P., Pettit, A. R., O'Sullivan, B. and Thomas, R. (2007), Antigen-specific suppression of established arthritis in mice by dendritic cells deficient in NF-κB. Arthritis & Rheumatism, 56: 2255–2266. doi: 10.1002/art.22655
- Issue published online: 28 JUN 2007
- Article first published online: 28 JUN 2007
- Manuscript Accepted: 16 MAR 2007
- Manuscript Received: 22 MAY 2006
- National Health and Medical Research Council of Australia. Grant Numbers: 210237, 351439
- Princess Alexandra Hospital Foundation
- Arthritis Queensland
NF-κB inhibitors applied to animal models of rheumatoid arthritis (RA) demonstrate the important role of NF-κB in the production of mediators of inflammation in the joint and their antiinflammatory effects. Because NF-κB is involved in the differentiation, activation, and survival of almost all cells, its prolonged inhibition might have unwanted adverse effects. Therefore, we sought to apply NF-κB inhibitors more specifically, targeting dendritic cell (DC) differentiation, in order to influence the outcome of the autoimmune response, rather than to produce a broad antiinflammatory effect. We tested whether DCs treated with the NF-κB inhibitor BAY 11-7082 and exposed to arthritogenic antigen would suppress established arthritis in C57BL/6 mice.
Antigen-induced arthritis was generated in C57BL/6 mice by injection of methylated bovine serum albumin (mBSA). After mBSA challenge, mouse knee joints were injected with antigen-exposed BAY 11-7082–treated DCs or with soluble tumor necrosis factor receptor (sTNFR). Intraarticular injection of interleukin-1 (IL-1) was used to induce disease flare.
Inflammation and erosion were suppressed in mice that received mBSA-exposed BAY 11-7082–treated DCs, but not in those that received keyhole limpet hemocyanin–exposed BAY 11-7082–treated DCs. Clinical improvement was dependent on IL-10 and was associated with antigen-specific suppression of the delayed-type hypersensitivity (DTH) reaction and switching of anti-mBSA antibody isotype from IgG2b to IgG1 and IgA. Suppression of the DTH reaction or arthritic disease was not impaired by concomitant administration of sTNFR. Suppression could be reversed with intraarticular administration of IL-1β and could be restored by a second injection of mBSA-exposed BAY 11-7082–treated DCs.
BAY 11-7082–treated DCs induce antigen-specific immune suppression in this model of inflammatory arthritis, even after full clinical expression of the disease. Such DCs have potential as antigen-specific therapy for autoimmune inflammatory arthritis, including RA.