CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy in experimental autoimmune encephalomyelitis

doi:10.1186/1476-9255-6-32

Journal of Inflammation

Volume 6

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Wang Y
Cui L
Gonsiorek W
Min SH
Anilkumar G
Rosenblum S
Kozlowski J
Lundell D
Fine JS
Grant EP

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Wang Y
Cui L
Gonsiorek W
Min SH
Anilkumar G
Rosenblum S
Kozlowski J
Lundell D
Fine JS
Grant EP
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Research

CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy in experimental autoimmune encephalomyelitis

Yuanfan Wang¹ , Long Cui¹ , Waldemar Gonsiorek¹^,2 , Soo-Hong Min¹ , Gopinadhan Anilkumar¹ , Stuart Rosenblum¹ , Joseph Kozlowski¹ , Daniel Lundell¹ , Jay S Fine¹^,2 and Ethan P Grant¹

¹Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA

²Hoffmann-La Roche, Inc., 340 Kingsland St., Nutley, NJ 07110, USA

author email corresponding author email

Journal of Inflammation 2009, 6:32doi:10.1186/1476-9255-6-32


Published:	11 November 2009

Abstract

Background

CCR2 plays a key role in regulating monocyte trafficking to sites of inflammation and therefore has been the focus of much interest as a target for inflammatory disease.

Methods

Here we examined the effects of CCR2 blockade with a potent small molecule antagonist to determine the pharmacodynamic consequences on the peripheral blood monocyte compartment in the context of acute and chronic inflammatory processes.

Results

We demonstrate that CCR2 antagonism in vivo led to a rapid decrease in the number of circulating Ly6C^himonocytes and that this decrease was largely due to the CXCR4-dependent sequestration of these cells in the bone marrow, providing pharmacological evidence for a mechanism by which monocyte dynamics are regulated in vivo. CCR2 antagonism led to an accumulation of circulating CCL2 and CCL7 levels in the blood, indicating a role for CCR2 in regulating the levels of its ligands under homeostatic conditions. Finally, we show that the pharmacodynamic changes due to CCR2 antagonism were apparent after chronic dosing in mouse experimental autoimmune encephalomyelitis, a model in which CCR2 blockade demonstrated a dramatic reduction in disease severity, manifest in a reduced accumulation of monocytes and other cells in the CNS.

Conclusion

CCR2 antagonism in vivo has tractable pharmacodynamic effects that can be used to align target engagement with biologic effects on disease activity.