Targeting CXCR3 reduces ligand-induced T-cell activation but not development of lung allergic responses

Ann Allergy Asthma Immunol. 2011 Aug;107(2):145-53. doi: 10.1016/j.anai.2011.04.013. Epub 2011 Jun 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / immunology
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Immunotherapy*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Pneumonia / chemically induced
  • Pneumonia / drug therapy*
  • Pneumonia / immunology
  • Pneumonia / physiopathology*
  • Receptors, CXCR3 / antagonists & inhibitors*
  • Respiratory Function Tests
  • Th2 Cells / immunology
  • Th2 Cells / metabolism*

Substances

  • CXCR3 protein, human
  • Receptors, CXCR3