Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Polyphor Ltd, Allschwil, Switzerland.
Immun Inflamm Dis. 2017 Jun;5(2):98-108. doi: 10.1002/iid3.147. Epub 2017 Feb 2.
Asthma 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.
C57BL6 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.
Treatment 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.
Blockade 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.
哮喘是全球范围内的主要健康负担，目前尚无任何疗法能够预防疾病的发生。生命早期发生严重呼吸道副黏病毒感染已被证实会大大增加患哮喘的风险。我们有一个模拟人类疾病的严重呼吸道副黏病毒感染（仙台病毒，SeV）的小鼠模型，该模型需要早期表达细胞因子 CCL28 来驱动病毒后气道疾病的发展。CCL28 的已知受体是 CCR3 和 CCR10。然而，尚不清楚阻断这些受体是否会预防病毒后气道疾病的发生。本研究的目的是确定 CCR10 的蛋白表位模拟拮抗剂 POL7085 的治疗是否能为预防病毒后气道疾病提供足够的保护。
C57BL6 小鼠用 SeV 或 UV 失活的 SeV 接种。在接种后 3-19 天（PI），小鼠每天皮下给予 POL7085 或生理盐水，或每隔一天给予抗 CCL28 mAb。在 PI 的第 8、10 和 12 天测量支气管肺泡细胞因子、血清 IgE 和肺细胞成分。在 PI 的第 21 天测量气道对乙酰甲胆碱的高反应性和粘液细胞化生。
用抗 CCL28 或 POL7085 治疗可显著减轻 SeV 感染后气道高反应性和粘液细胞化生的发展。病毒后气道疾病的预防与早期固有免疫细胞的减少有关，但似乎与 IL-13 或 IgE 的减少无关。
在急性严重呼吸道副黏病毒感染期间阻断 CCL28 或 CCR10 足以预防病毒后气道疾病的发生。然而，其作用机制尚不清楚，需要进一步探索。
