Abstract
Antagonism of the chemokine receptor CXCR3 is hypothesized to reduce viral exacerbations of asthma and COPD by reducing recruitment of cytotoxic CD8+ T-cells to the lung. Here we describe the pre-clinical in vivo characterization of a highly selective and potent CXCR3 antagonist, Compound X (CX).
Methods: Female BALB/c mice were used. Pseudomonas aeruginosa Lipopolysaccharide (paLPS, 5 mg/mL) was administered via inhalation. H1N1 (40 PFU/mouse) was administered intranasally. CX or vehicle was administered via oral gavage twice daily. CD8+ T-cells in BAL fluid were quantified by flow cytometry. Enhanced pause (Penh) was determined with whole body plethysmography.
Results: Administration of CX (3-30 mg/kg) dose dependently decreased recruitment of CD8+ T-cells into BAL fluid at 72 hours after challenge with paLPS. A maximal effect of 80% inhibition (p<0.001) was achieved with 30 mg/kg CX compared to vehicle control. In a mouse model of H1N1 infection administration of CX at 60 mg/kg caused significant reductions in the % CD8+ T-cells on days 3 (100%, p<0.001), 5 (80%, p<0.001) and 7 (26%, p<0.05). H1N1 viral titres were not affected by CX treatment. Whole body plethysmography measured on days 1, 3, 5 and 7 showed a significant rise in Penh at all times following H1N1 infection. Significant reductions in Penh were observed in the CX treatment group on days 5 and 7.
Conclusions: CX strongly suppressed CD8+ T-cell recruitment in vivo following paLPS or H1N1 challenge. CX was well tolerated and did not affect H1N1 viral titres. Finally, CX significantly reduced Penh at the later time points following H1N1 infection, indicating that CXCR3 antagonism can provide benefit during a viral infection.
- © 2014 ERS