Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI
Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI
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DOI：
10.4049/jimmunol.165.6.3418
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发表时间：
2000-09-15
影响因子：
4.4
通讯作者：
Lewis, DB
中科院分区：
文献类型：
--
作者：
Dabbagh, K;Xiao, Y;Lewis, DB
过敏原诱发的哮喘以慢性肺部炎症、可逆性支气管收缩和气道对刺激性刺激的高反应性为特征。多种cc趋化因子是由肺组织对哮喘患者或实验致敏的啮齿动物的局部过敏原挑战作出反应而产生的，这些趋化因子将白细胞从循环中吸引到肺实质和气道中，并可能改变非趋化功能。为了确定局部肺内cc趋化因子阻断对哮喘的治疗潜力，我们通过鼻内给药重组天花病毒衍生的病毒cc趋化因子抑制蛋白（vCCI），该蛋白在体外与啮齿动物和人类cc趋化因子具有高亲和力并中和其生物活性。呼吸道给予vCCI可显著改善肺生理功能，减少气道和肺实质炎症，而vCCI对循环总IgE或过敏原特异性IgE水平、外周淋巴结T细胞产生的过敏原特异性细胞因子、局部过敏原攻击后的腹膜炎症无显著影响。表明vCCI不会改变全身ag特异性免疫或肺外部位的化学吸引。总之，这些发现强调了肺内cc趋化因子在哮喘发病机制中的重要性，以及通用和局部cc趋化因子阻断对哮喘和其他局部产生cc趋化因子的慢性疾病的治疗潜力。
Allergen-induced asthma is characterized by chronic pulmonary inflammation, reversible bronchoconstriction, and airway hyperreactivity to provocative stimuli. Multiple CC-chemokines, which are produced by pulmonary tissue in response to local allergen challenge of asthmatic patients or experimentally sensitized rodents, chemoattract leukocytes from the circulation into the lung parenchyma and airway, and may also modify nonchemotactic function. To determine the therapeutic potential of local intrapulmonary CC-chemokine blockade to modify asthma, a recombinant poxvirus-derived viral CC-chemokine inhibitor protein (vCCI), which binds with high affinity to rodent and human CC-chemokines in vitro and neutralizes their biological activity, was administered by the intranasal route. Administration of vCCI to the respiratory tract resulted in dramatically improved pulmonary physiological function and decreased inflammation of the airway and the lung parenchyma, In contrast, vCCI had no significant effect on the circulating levels of total or allergen-specific IgE, allergen-specific cytokine production by peripheral lymph node T cells, or peritoneal inflammation after local allergen challenge, indicating that vCCI did not alter systemic Ag-specific immunity or chemoattraction at extrapulmonary sites. Together, these findings emphasize the importance of intrapulmonary CC-chemokines in the pathogenesis of asthma, and the therapeutic potential of generic and local CC-chemokine blockade for this and other chronic diseases in which CC-chemokines are locally produced.