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

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• 作者：Yuanfan Wang (1)
  Long Cui (1)
  Waldemar Gonsiorek (1) (2)
  Soo-Hong Min (1)
  Gopinadhan Anilkumar (1)
  Stuart Rosenblum (1)
  Joseph Kozlowski (1)
  Daniel Lundell (1)
  Jay S Fine (1) (2)
  Ethan P Grant (1)
  
• 刊名：Journal of Inflammation
• 出版年：2009
• 出版时间：December 2009
• 年：2009
• 卷：6
• 期：1
• 全文大小：2347KB
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• 作者单位：Yuanfan Wang (1)
  Long Cui (1)
  Waldemar Gonsiorek (1) (2)
  Soo-Hong Min (1)
  Gopinadhan Anilkumar (1)
  Stuart Rosenblum (1)
  Joseph Kozlowski (1)
  Daniel Lundell (1)
  Jay S Fine (1) (2)
  Ethan P Grant (1)
  
  1. Schering-Plough Research Institute, 2015 Galloping Hill Road, 07033, Kenilworth, NJ, USA
  2. Hoffmann-La Roche, Inc, 340 Kingsland St, 07110, Nutley, NJ, USA
  
• ISSN：1476-9255

文摘

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 Ly6Chi monocytes 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.