Targeting of Gr-1+,CCR2+ monocytes in collagen-induced arthritis.
OBJECTIVE
The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen-induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proinflammatory effects, how these effects can be avoided, and whether CCR2+ monocytes are useful targets in the treatment of arthritis.


METHODS
Arthritis was induced in DBA/1 mice by immunization with type II collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay.


RESULTS
Crosslinkage of CCR2 activated basophils to release interleukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1+,CCR2+ monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen-induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.


CONCLUSIONS
These results show that depletion of CCR2+ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dose-dependent proinflammatory effects of CCR2 mAb are taken into account.
Brühl
Hilke
H
Regensburg University Medical Center, Regensburg, Germany.
Cihak
Josef
J
Plachý
Jirí
J
Kunz-Schughart
Leoni
L
Niedermeier
Marianne
M
Denzel
Andrea
A
Rodriguez Gomez
Manuel
M
Talke
Yvonne
Y
Luckow
Bruno
B
Stangassinger
Manfred
M
Mack
Matthias
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001168:Arthritis / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology*; D001491:Basophils / Q000276:immunology; D024043:Collagen Type II / Q000008:administration & dosage; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000276:immunology*; D054390:Receptors, CCR2 / Q000096:biosynthesis* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D015850:Interleukin-6; D054390:Receptors, CCR2