title: Targeting CXCR3 reduces ligand-induced T-cell activation but not development of lung allergic responses.
abstract: BACKGROUND
  Asthma is a chronic airway inflammatory disease that is associated with a large influx of inflammatory cells. Several chemokines and chemokine receptors play critical roles in the development of allergic airway inflammation.
  
  
  OBJECTIVE
  Because polarized human T(H)2 cells express a functional CXCR3 chemokine receptor, we evaluated the effects of a selective CXCR3 inhibitor in a mouse model of allergic airway disease.
  
  
  METHODS
  Ovalbumin-specific CD8(+) T effector cells were generated from OT-1 mice in the presence of interleukin 2. The activity of a CXCR3 inhibitor was examined in vitro by monitoring Ca(2+) influx after receptor ligation. In vivo, the activity was assessed in sensitized and challenged mice by monitoring airway function, inflammatory parameters, including cellular infiltrates and cytokines in the bronchoalveolar lavage fluid.
  
  
  RESULTS
  Approximately 40% of CD8(+) T effector cells expressed the CXCR3 receptor. In vitro, CXCR3 antagonism reduced Ca(2+) influx after receptor engagement. In contrast, the CXCR3 antagonist had little to no effect on airway function or inflammatory parameters despite adequate exposure levels.
  
  
  CONCLUSIONS
  CXCR3 antagonism did not prevent allergen-induced airway hyperresponsiveness or airway inflammation in a mouse allergy model despite having activity in in vitro functional assays.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Yi
authors.initials: Y
authors.lastname: Jia
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: MaryAnn L
authors.initials: ML
authors.lastname: Cox
authors.forename: Jay S
authors.initials: JS
authors.lastname: Fine
authors.forename: Stuart
authors.initials: S
authors.lastname: Rosenblum
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundel
authors.forename: Chung-Her
authors.initials: CH
authors.lastname: Jenh
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Manfra
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology*; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D012129:Respiratory Function Tests; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: C515187:CXCR3 protein, human; D054367:Receptors, CXCR3