Antigen-specific suppression of established arthritis in mice by dendritic cells deficient in NF-kappaB.
OBJECTIVE
NF-kappaB inhibitors applied to animal models of rheumatoid arthritis (RA) demonstrate the important role of NF-kappaB in the production of mediators of inflammation in the joint and their antiinflammatory effects. Because NF-kappaB 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-kappaB 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-kappaB inhibitor BAY 11-7082 and exposed to arthritogenic antigen would suppress established arthritis in C57BL/6 mice.


METHODS
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.


RESULTS
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-1beta and could be restored by a second injection of mBSA-exposed BAY 11-7082-treated DCs.


CONCLUSIONS
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.
Martin
Ela
E
University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Capini
Christelle
C
Duggan
Emily
E
Lutzky
Viviana P
VP
Stumbles
Philip
P
Pettit
Allison R
AR
O'Sullivan
Brendan
B
Thomas
Ranjeny
R
D000818:Animals; D000941:Antigens; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D006968:Hypersensitivity, Delayed; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000941:Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D012710:Serum Albumin, Bovine