POL7085 or anti-CCL28 treatment inhibits development of post-paramyxoviral airway disease

Abstract

IntroductionAsthma is major health burden throughout the world, and there are no therapies that have been shown to be able to prevent the development of disease. A severe respiratory paramyxoviral infection early in life has been demonstrated to greatly increase the risk of developing asthma. We have a mouse model of a severe respiratory paramyxoviral infection (Sendai virus, SeV) that mimics human disease, and requires early expression of the cytokine CCL28 to drive the development of post‐viral airway disease. The known receptors for CCL28 are CCR3 and CCR10. However, it is not known if blockade of these receptors will prevent the development of post‐viral airway disease. The objective of this study was to determine if treatment with a protein epitope mimetic antagonist of CCR10, POL7085, will provide sufficient protection against the development of post‐viral airway disease.MethodsC57BL6 mice were inoculated with SeV or UV inactivated SeV. From day 3–19 post inoculation (PI), mice were subcutaneously administered daily POL7085 or saline, or every other day anti‐CCL28 mAb. On days 8, 10, and 12 PI bronchoalveolar cytokines, serum IgE, and lung cellular constituents were measured. At day 21 PI airway hyper‐reactivity to methacholine and mucous cell metaplasia was measured.ResultsTreatment with either anti‐CCL28 or POL7085 significantly reduced development of airway hyper‐reactivity and mucous cell metaplasia following SeV infection. The prevention of post‐viral airway disease was associated with early reductions in innate immune cells, but did not appear to be due to a reduction in IL‐13 or IgE.ConclusionsBlockade of CCL28 or CCR10 during an acute severe respiratory paramyxoviral infection is sufficient to prevent the development of post‐viral airway disease. However, the mechanism of action is unclear and requires further exploration.

Deficiency of Stomach-Type Claudin-18 in Mice Induces Gastric Tumor Formation Independent of H pylori Infection

“…(Figure 4 D ). To further examine CCL28’s contribution to the stCldn18–/– mouse gastritis, POL7085, an inhibitor of the CCL28-CCR10 cascade,44, 45 was administered to the stCldn18–/– mice. After 1 week of POL7085 administration, the expression levels of inflammation-related genes such as CXCL5, NF-kB, and IKKβ were dramatically decreased in the middle-aged stCldn18–/– mice (around 50 w.o.)…”