Targeting of Gr-1+,CCR2+ monocytes in collagen-induced arthritis.

Abstract

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.

CONCLUSION:

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.

• Authors: Hilke Brühl, Josef Cihak, Jirí Plachý, Leoni Kunz-Schughart, Marianne Niedermeier, Andrea Denzel, Manuel Rodriguez Gomez, Yvonne Talke, Bruno Luckow, Manfred Stangassinger, Matthias Mack
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 56 Issue 9 Pg. 2975-85 (Sep 2007) ISSN: 0004-3591 [Print] United States
• PMID: 17763443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Collagen Type II
• Interleukin-6
• Receptors, CCR2

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Arthritis (drug therapy, etiology, immunology)
• Basophils (immunology)
• Collagen Type II (administration & dosage)
• Interleukin-6 (biosynthesis)
• Mice
• Mice, Inbred DBA
• Monocytes (immunology)
• Receptors, CCR2 (biosynthesis, immunology)