title: CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy in experimental autoimmune encephalomyelitis.
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 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.
  
  
  CONCLUSIONS
  CCR2 antagonism in vivo has tractable pharmacodynamic effects that can be used to align target engagement with biologic effects on disease activity.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. ethan.grant@spcorp.com.
authors.forename: Yuanfan
authors.initials: Y
authors.lastname: Wang
authors.forename: Long
authors.initials: L
authors.lastname: Cui
authors.forename: Waldemar
authors.initials: W
authors.lastname: Gonsiorek
authors.forename: Soo-Hong
authors.initials: SH
authors.lastname: Min
authors.forename: Gopinadhan
authors.initials: G
authors.lastname: Anilkumar
authors.forename: Stuart
authors.initials: S
authors.lastname: Rosenblum
authors.forename: Joseph
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.forename: Ethan P
authors.initials: EP
authors.lastname: Grant