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Therapeutic benefits of recombinant alpha1-antitrypsin IgG1 Fc-fusion protein in experimental emphysema
Respiratory Research ( IF 4.7 ) Pub Date : 2021-07-16 , DOI: 10.1186/s12931-021-01784-y
Katsuyuki Takeda 1, 2 , Soo-Hyun Kim 1, 3 , Anthony Joetham 1 , Irina Petrache 4 , Erwin W Gelfand 1
Affiliation  

Alpha-1 antitrypsin (AAT) is a major serine protease inhibitor. AAT deficiency (AATD) is a genetic disorder characterized by early-onset severe emphysema. In well-selected AATD patients, therapy with plasma-derived AAT (pAAT), “augmentation therapy”, provides modest clinical improvement but is perceived as cumbersome with weekly intravenous infusions. Using mouse models of emphysema, we compared the effects of a recombinant AAT-IgG1 Fc-fusion protein (AAT-Fc), which is expected to have a longer half-life following infusion, to those of pAAT. In an elastase model of emphysema, mice received a single intratracheal instillation of porcine pancreatic elastase (PPE) or human leucocyte elastase (hLE). AAT-Fc, pAAT, or vehicle was administered intraperitoneally 1 day prior to or 3 weeks following elastase instillation. Lung function and histology assessments were performed at 7 and 32 days after elastase instillation. In a cigarette smoke (CS) model of emphysema, mice were exposed to CS daily, 5 days a week, for 6 months and AAT-Fc, pAAT, or vehicle were administered every 10 days during the last 3 months of CS exposure. Assessments were performed 3 days after the last CS exposure. Immune responses to lung elastin peptide (EP) and the effects of AAT-Fc or pAAT treatment on dendritic cell (DC) function were determined ex vivo. Both elastase instillation and CS exposure triggered emphysema-like alveolar enlargement, increased lung compliance, and increased markers of inflammation compared to controls. Administration of AAT-Fc either prior to or following elastase instillation or during CS exposure provided greater protection than pAAT against alveolar enlargement, lung dysfunction, and airway inflammation. When challenged ex vivo with EP, spleen mononuclear cells from elastase-exposed mice exhibited dose-dependent production of IFNγ and IL-17, suggesting immune reactivity. In co-culture experiments with splenic CD4+ T cells isolated from elastase-exposed mice, AAT-Fc treatment prior to EP-priming of bone marrow-derived dendritic cells inhibited the production of IFNγ and IL-17. Compared to pAAT, AAT-Fc more effectively prevented or attenuated elastase- and CS-induced models of emphysema. These effects were associated with immunomodulatory effects on DC activity. AAT-Fc may provide a therapeutic option to individuals with AATD- and CS-induced emphysema.

中文翻译:


重组 α1-抗胰蛋白酶 IgG1 Fc 融合蛋白对实验性肺气肿的治疗效果



Alpha-1 抗胰蛋白酶 (AAT) 是一种主要的丝氨酸蛋白酶抑制剂。 AAT 缺乏症 (AATD) 是一种遗传性疾病,其特征是早发性严重肺气肿。在精心挑选的 AATD 患者中,血浆来源的 AAT (pAAT) 治疗(“增强治疗”)可提供一定的临床改善,但每周静脉输注被认为很麻烦。使用肺气肿小鼠模型,我们比较了重组 AAT-IgG1 Fc 融合蛋白 (AAT-Fc) 与 pAAT 的效果,预计该蛋白输注后半衰期更长。在肺气肿弹性蛋白酶模型中,小鼠接受单次气管内滴注猪胰腺弹性蛋白酶(PPE)或人白细胞弹性蛋白酶(hLE)。在弹性蛋白酶滴注前1天或滴注后3周腹膜内施用AAT-Fc、pAAT或载体。弹性蛋白酶滴注后7天和32天进行肺功能和组织学评估。在肺气肿的香烟烟雾 (CS) 模型中,小鼠每天暴露于 CS,每周 5 天,持续 6 个月,并在最后 3 个月的 CS 暴露期间每 10 天施用 AAT-Fc、pAAT 或载体。最后一次 CS 暴露后 3 天进行评估。离体测定了对肺弹性蛋白肽(EP)的免疫反应以及AAT-Fc或pAAT治疗对树突细胞(DC)功能的影响。与对照组相比,弹性蛋白酶滴注和 CS 暴露均引发肺气肿样肺​​泡扩大、肺顺应性增加和炎症标志物增加。在弹性蛋白酶滴注之前或之后或在CS暴露期间施用AAT-Fc提供比pAAT更好的保护,以防止肺泡扩大、肺功能障碍和气道炎症。 当用 EP 进行离体攻击时,暴露于弹性蛋白酶的小鼠的脾脏单核细胞表现出剂量依赖性的 IFNγ 和 IL-17 产生,表明免疫反应性。在使用从暴露于弹性蛋白酶的小鼠中分离出的脾 CD4+ T 细胞的共培养实验中,在对骨髓源性树突细胞进行 EP 引发之前进行 AAT-Fc 处理可抑制 IFNγ 和 IL-17 的产生。与 pAAT 相比,AAT-Fc 更有效地预防或减弱弹性蛋白酶和 CS 诱导的肺气肿模型。这些作用与 DC 活性的免疫调节作用有关。 AAT-Fc 可以为患有 AATD 和 CS 诱导的肺气肿的个体提供一种治疗选择。
更新日期:2021-07-16
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