Journal of Allergy and Clinical Immunology最新文献

英文中文

Oral mucosa effectively protects against peanut allergy in mice 口腔黏膜能有效防止小鼠对花生过敏

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.05.012

Background

Oral consumption of peanut products early in life reduces the incidence of peanut allergy in children. However, little is known about whether exposure via the oral mucosa alone is sufficient or whether the gastrointestinal tract must be engaged to protect against peanut allergy.

Objective

We used a mouse model and examined the effects of peanut allergen administration to only the oral cavity on allergy development induced by environmental exposure.

Methods

Naive BALB/c mice were administered peanut flour (PNF) sublingually, followed by epicutaneous exposure to PNF to mimic a human condition. The sublingual volume was adjusted to engage only the oral cavity and prevent it from reaching the esophagus or gastrointestinal tract. The efficacy was evaluated by examining the anaphylactic response, antibody titers, and T follicular helper cells.

Results

The mice exposed epicutaneously to PNF developed peanut allergy, as demonstrated by increased plasma levels of peanut-specific IgE and the manifestation of acute systemic anaphylaxis following intraperitoneal challenge with peanut extract. The development of peanut allergy was suppressed when mice had been given PNF sublingually before epicutaneous exposure. There were fewer T follicular helper cells in the skin-draining lymph nodes of mice that received sublingual PNF than in the mice that received PBS. Suppression of IgE production was observed with sublingual PNF at 1/10 of the intragastric PNF dose.

Conclusion

Administration of peanut allergens only to the oral cavity effectively prevents the development of peanut allergy. The capacity of the oral mucosa to promote immunologic tolerance needs to be evaluated further to prevent food allergy.

背景早期口服花生产品可降低儿童花生过敏的发病率。我们使用小鼠模型，研究了仅在口腔内给予花生过敏原对环境暴露诱发的过敏发展的影响。方法给无知的 BALB/c 小鼠舌下含服花生粉 (PNF)，然后模仿人类的情况皮外暴露于 PNF。舌下给药量经过调整，仅用于口腔，防止其进入食道或胃肠道。通过检测过敏反应、抗体滴度和 T 滤泡辅助细胞来评估疗效。结果小鼠舌下接触 PNF 后出现花生过敏，表现为血浆中花生特异性 IgE 水平升高，腹腔注射花生提取物后出现急性全身过敏反应。如果小鼠在皮外暴露前舌下含服 PNF，则花生过敏的发生会受到抑制。与接受 PBS 的小鼠相比，舌下含服 PNF 的小鼠皮肤引流淋巴结中的 T 滤泡辅助细胞更少。舌下含服 PNF 可抑制 IgE 的产生，其剂量为胃内含服 PNF 剂量的 1/10。口腔粘膜促进免疫耐受的能力需要进一步评估，以预防食物过敏。

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引用次数: 0

The Editors’ Choice 编辑推荐

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.08.012

引用次数: 0

Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: Systematic review and meta-analysis of randomized clinical trials 白三烯受体拮抗剂作为荨麻疹抗组胺药的附加疗法：随机临床试验的系统回顾和荟萃分析。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.05.026

Background

The benefits and harms of adding antileukotrienes to H₁ antihistamines (AHs) for the management of urticaria (hives, itch, and/or angioedema) remain unclear.

Objective

We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with AHs versus AHs alone for acute and chronic urticaria.

Methods

As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched Medline, Embase, Central, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, US Food and Drug Administration, and European Medicines Agency databases from inception to December 18, 2023, for randomized controlled trials (RCTs) evaluating antileukotrienes and AHs versus AHs alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. The study was registered at the Open Science Framework (osf.io/h2bfx/).

Results

Thirty-four RCTs enrolled 3324 children and adults. Compared to AHs alone, the combination of a leukotriene receptor antagonist with AHs probably modestly reduces urticaria activity (mean difference, −5.04; 95% confidence interval, −6.36 to −3.71; 7-day urticaria activity score) with moderate certainty. We made similar findings for itch and wheal severity as well as quality of life. Adverse events were probably not different between groups (moderate certainty); however, no RCT reported on neuropsychiatric adverse events.

Conclusion

Among patients with urticaria, adding leukotriene receptor antagonists to AHs probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with leukotriene receptor antagonists is small and uncertain.

背景：在治疗荨麻疹（荨麻疹、瘙痒和/或血管性水肿）时，在H1-抗组胺药物中添加抗白三烯类药物的利弊尚不清楚：我们试图系统地综合抗白三烯类药物与 H1-抗组胺药联合治疗急性和慢性荨麻疹与单独使用 H1-抗组胺药治疗急性和慢性荨麻疹的疗效：作为更新美国过敏、哮喘和免疫学学会和美国过敏、哮喘和免疫学学院实践参数联合工作组荨麻疹指南的一部分，我们检索了MEDLINE、Embase、CENTRAL、LILACS、WPRIM、IBECS、ICTRP、CBM、CNKI、VIP、万方、FDA 和 EMA 数据库，以评估抗白三烯类药物和 H1-抗组胺药与单独使用 H1-抗组胺药治疗荨麻疹患者的随机对照试验 (RCT)。配对审稿人独立筛选引文、提取数据并评估偏倚风险。随机效应模型汇总了荨麻疹活动、瘙痒、喘息、睡眠、生活质量和危害的效应估计值。GRADE方法为证据的确定性评级提供了依据。开放科学框架注册：https://osf.io/h2bfx/.Results：34项RCT共招募了3324名儿童和成人。与单独使用 H1-抗组胺药相比，白三烯受体拮抗剂 (LTRA) 与 H1-抗组胺药联合使用可能会适度降低荨麻疹的活动性（平均差异：-5.04，95%C）：-平均差异：-5.04，95%CI -6.36 至 -3.71；7 天荨麻疹活动评分）。在瘙痒和荨麻疹严重程度以及生活质量方面，我们也得出了类似的结论。各组间的不良事件可能没有差异（中等确定性），但没有一项研究报告了神经精神不良事件：结论：在荨麻疹患者中，在H1-抗组胺药物中添加LTRAs可能会适度改善荨麻疹的活动性，但总体不良事件几乎不会增加。在这一人群中，LTRAs增加的神经精神不良事件风险较小，且不确定。

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引用次数: 0

Single-cell RNA-sequencing of human eosinophils in allergic inflammation in the esophagus 食管过敏性炎症中人类嗜酸性粒细胞的单细胞 RNA 测序

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.05.029

Background

Eosinophils are elusive cells involved in allergic inflammation. Single-cell RNA-sequencing (scRNA-seq) is an emerging approach to deeply characterize cellular properties, heterogeneity, and functionality.

Objectives

We sought to comprehensively characterize the transcriptome and biological functions of human eosinophils at a site of severe allergic inflammation in the esophagus (ie, eosinophilic esophagitis [EoE]).

Methods

We employed a gravity-based scRNA-seq methodology to sequence blood eosinophils from patients with EoE and control individuals compared to a reanalyzed public scRNA-seq dataset of human esophageal eosinophils of EoE patients. We used flow cytometry, immunostaining, and a stimulation assay to verify mRNA findings.

Results

In total, scRNA-seq was obtained from 586 eosinophils (188 from blood [n = 6 individuals] and 398 from esophagus [n = 6 individuals]). The esophageal eosinophils were composed of a population of activated eosinophils (enriched in 659 genes compared with peripheral blood–associated eosinophils) and a small population of eosinophils resembling peripheral blood eosinophils (enriched in 62 genes compared with esophageal eosinophils). Esophageal eosinophils expressed genes involved in sensing and responding to diverse stimuli, most notably IFN-γ, IL-10, histamine and leukotrienes, and succinate. Esophageal eosinophils were most distinguished from other esophageal populations by gene expression of the receptors CCR3, HRH4, SUCNR1, and VSTM1; transcription factors CEBPE, OLIG1, and OLIG2; protease PRSS33; and the hallmark eosinophil gene CLC. A web of bidirectional eosinophil interactions with other esophageal populations was derived. Comparing esophageal eosinophils and mast cells revealed that esophageal eosinophils expressed genes involved in DNAX-activation protein-12 (also known as TYROBP) interactions, IgG receptor-triggered events, immunoregulation, and IL-10 signaling.

Conclusions

In EoE, esophageal eosinophils exist as 2 populations, a minority population resembling blood eosinophils and the other population characterized by high de novo transcription of diverse sensing receptors and inflammatory mediators readying them to potentially intersect with diverse cell types.

背景：嗜酸性粒细胞是参与过敏性炎症的难以捉摸的细胞。单细胞 RNA 测序（scRNA-seq）是深入研究细胞特性、异质性和功能的一种新兴方法：全面描述食管严重过敏性炎症部位（即嗜酸性粒细胞食管炎（EoE））人类嗜酸性粒细胞的转录组和生物功能：我们采用基于重力的 scRNA-seq 方法对嗜酸性粒细胞食管炎患者和对照组的血液嗜酸性粒细胞进行测序，并与重新分析的嗜酸性粒细胞食管炎患者食管嗜酸性粒细胞的公共 scRNA-seq 数据集进行比较。我们使用流式细胞术、免疫染色法和刺激试验来验证 mRNA 研究结果：我们总共从 586 个嗜酸性粒细胞（188 个来自血液[n=6 人]，398 个来自食管[n=6 人]）中获得了 scRNA-seq。食管嗜酸性粒细胞由活化的嗜酸性粒细胞群（与外周血相关嗜酸性粒细胞相比，富集了 659 个基因）和一小部分与外周血嗜酸性粒细胞相似的嗜酸性粒细胞群（与食管嗜酸性粒细胞相比，富集了 62 个基因）组成。食管嗜酸性粒细胞表达的基因涉及对各种刺激的感知和反应，其中最主要的是干扰素、白细胞介素 10、组胺、白三烯和琥珀酸。食管嗜酸性粒细胞与其他食管群体的最大区别在于受体 CCR3、HRH4、SUCNR1 和 VSTM1；转录因子 CEBPE、OLIG1 和 OLIG2；蛋白酶 PRSS33 和标志性嗜酸性粒细胞基因 CLC 的基因表达。得出了嗜酸性粒细胞与其他食管人群之间的双向互动网络。比较食管嗜酸性粒细胞和肥大细胞发现，食管嗜酸性粒细胞表达的基因涉及 DAP12 相互作用、IgG 受体触发事件、免疫调节和 IL-10 信号转导：结论：在咽喉炎患者中，食管嗜酸性粒细胞有两个种群，一个少数种群与血液中的嗜酸性粒细胞相似，另一个种群的特点是能从头转录多种传感受体和炎症介质，使其有可能与多种细胞类型发生交叉。

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引用次数: 0

Human angiotensin-converting enzyme 2–specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants 人类血管紧张素转换酶 2 特异性反义寡核苷酸可减少 SARS-CoV-2 变体的感染。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.06.007

Background

The Spike protein mutation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to decreased protective effect of various vaccines and mAbs, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin-converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Downregulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed on the basis of sequence data, require no delivery system, and can be administered locally.

Objective

We sought to design ASOs that can block SARS-CoV-2 by downregulating ACE2 in human airway.

Methods

ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASO-pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels.

Results

ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore, they efficiently suppressed virus replication of 3 different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also downregulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathologic changes in lungs, and increased survival of mice.

Conclusions

ACE2-targeting ASOs can effectively block SARS-CoV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.

背景：SARS-CoV-2 的穗状病毒蛋白变异导致各种疫苗和单克隆抗体的保护效果下降，这表明通过靶向宿主因子阻断 SARS-CoV-2 感染将使疗法对病毒变异更有抵抗力。血管紧张素转换酶 2（ACE2）是 SARS-CoV-2 及其变种以及许多其他冠状病毒的宿主受体。下调呼吸道中 ACE2 的表达可预防病毒感染。反义寡核苷酸（ASOs）可以根据序列数据合理设计，不需要传递系统，而且可以局部给药：我们试图设计能通过下调人体气道中 ACE2 来阻断 SARS-CoV-2 的 ASO：方法：采用生物信息学方法设计了ACE2靶向ASOs，并在细胞系中进行了筛选。方法：采用生物信息学方法设计了针对 ACE2 的 ASOs，并在细胞系中进行了筛选。在空气-液体界面培养的人原代鼻上皮细胞和人源化 ACE2 小鼠被用来检测 ACE2 的降低水平和 ASOs 的安全性。ASOs预处理过的鼻上皮细胞和小鼠受到感染，然后用来检测病毒感染水平：结果：ASOs 降低了细胞系和人类鼻上皮细胞中 ACE2 的 mRNA 和蛋白表达水平。此外，ASOs 还能有效抑制三种不同的 SARS-CoV-2 变种在人鼻上皮细胞中的病毒复制。在体内，ASOs 还能在人源化 ACE2 小鼠体内下调人 ACE2，从而减少病毒载量和肺部组织病理学变化，并提高小鼠的存活率：结论：ACE2 靶向 ASOs 能有效阻断 SARS-COV-2 感染。我们的研究为在高危人群中阻断 SARS-CoV-2 和其他 ACE2 靶向病毒提供了一种新方法。

{"title":"Human angiotensin-converting enzyme 2–specific antisense oligonucleotides reduce infection with SARS-CoV-2 variants","authors":"","doi":"10.1016/j.jaci.2024.06.007","DOIUrl":"10.1016/j.jaci.2024.06.007","url":null,"abstract":"<div><h3>Background</h3><div>The Spike protein mutation severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to decreased protective effect of various vaccines and mAbs, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin-converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Downregulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed on the basis of sequence data, require no delivery system, and can be administered locally.</div></div><div><h3>Objective</h3><div>We sought to design ASOs that can block SARS-CoV-2 by downregulating ACE2 in human airway.</div></div><div><h3>Methods</h3><div>ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASO-pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels.</div></div><div><h3>Results</h3><div>ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore, they efficiently suppressed virus replication of 3 different SARS-CoV-2 variants in human nasal epithelial cells. <em>In vivo</em>, ASOs also downregulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathologic changes in lungs, and increased survival of mice.</div></div><div><h3>Conclusions</h3><div>ACE2-targeting ASOs can effectively block SARS-CoV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mast cell–sensory neuron interactions under stress 压力下肥大细胞与感觉神经元的相互作用

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.05.032

引用次数: 0

Blockade of endolysosomal acidification suppresses TLR3-mediated proinflammatory signaling in airway epithelial cells 阻断内溶酶体酸化可抑制气道上皮细胞中由 TLR3 介导的促炎信号传导。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.05.031

Background

Endolysosomal compartments are acidic and contain low pH-dependent proteases, and these conditions are exploited by respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, for escaping into the cytosol. Moreover, endolysosomes contain various pattern recognition receptors (PRRs), which respond to virus-derived pathogen-associated molecular patterns (PAMPs) by production of proinflammatory cytokines/chemokines. However, excessive proinflammatory responses can lead to a potentially lethal cytokine storm.

Objectives

Here we investigated the endosomal PRR expression profile in primary human small airway epithelial cells (HSAECs), and whether blockade of endolysosomal acidification affects their cytokine/chemokine production after challenge with virus-derived stimulants.

Methods

HSAECs were exposed to stimulants mimicking virus-derived PAMPs, either in the absence or presence of compounds causing blockade of endolysosomal acidification, followed by measurement of cytokine expression and release.

Results

We show that Toll-like receptor 3 (TLR3) is the major endosomal PRR expressed by HSAECs, and that TLR3 expression is strongly induced by TLR3 agonists, but not by a range of other PRR agonists. We also demonstrate that TLR3 engagement with its agonists elicits a robust proinflammatory cytokine/chemokine response, which is profoundly suppressed through blockade of endolysosomal acidification, by bafilomycin A1, monensin, or niclosamide. Using TLR3 reporter cells, it was confirmed that TLR3 signaling is strongly induced by Poly(I:C) and that blockade of endolysosomal acidification efficiently blocked TLR3 signaling. Finally, we show that blockade of endolysosomal acidification causes a reduction in the levels of TLR3 mRNA and protein.

Conclusions

These findings show that blockade of endolysosomal acidification suppresses TLR3-dependent cytokine and chemokine production in HSAECs.

背景：内溶酶体是酸性的，含有低 pH 依赖性蛋白酶，SARS-CoV-2 和流感病毒等呼吸道病毒利用这些条件逃逸到细胞膜中。此外，内溶酶体含有各种模式识别受体（PRRs），可通过产生促炎细胞因子/趋化因子对源自病毒的病原体相关分子模式（PAMPs）做出反应。然而，过度的促炎反应可能会导致潜在的致命细胞因子风暴：目的：我们在此研究了原代人小气道上皮细胞（HSAECs）的内泌体 PRR 表达谱，以及阻断内泌体酸化是否会影响细胞因子/趋化因子在受到病毒刺激物挑战后的产生。方法：在没有或存在可阻断内泌体酸化的化合物的情况下，将 HSAECs 暴露于模拟病毒 PAMPs 的刺激物，然后测量细胞因子的表达和释放：结果：我们发现收费样受体 3（TLR3）是 HSAECs 表达的主要内溶酶体 PRR，TLR3 的表达受 TLR3 激动剂的强烈诱导，而不受一系列其他 PRR 激动剂的诱导。我们还证明，TLR3 与其激动剂接触会引起强烈的促炎细胞因子/趋化因子反应，而巴佛洛霉素 A1、莫能菌素或尼可刹米通过阻断内溶酶体酸化会极大地抑制这种反应。使用 TLR3 报告细胞证实，Poly(I:C) 能强烈诱导 TLR3 信号传导，而阻断内溶酶体酸化能有效阻断 TLR3 信号传导。最后，我们发现阻断内溶酶体酸化会导致 TLR3 mRNA 和蛋白质水平下降：这些研究结果表明，阻断溶酶体内酸化可抑制 HSAECs 中 TLR3 依赖性细胞因子和趋化因子的产生：临床意义：这些发现可用于旨在改善呼吸道病毒感染时细胞因子风暴的治疗策略。

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引用次数: 0

Breathing unequal: Unmasking the link between environmental justice, air pollution, and asthma severity 不平等的呼吸：揭开环境正义、空气污染和哮喘严重程度之间的联系。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.01.033

引用次数: 0

A novel inhalable nanobody targeting IL-4Rα for the treatment of asthma 用于治疗哮喘的新型可吸入纳米抗体靶向 IL-4Rα。

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.jaci.2024.05.027

Background

Inhalable biologics represent a promising approach to improve the efficacy and safety of asthma treatment. Although several mAbs targeting IL-4 receptor α chain (IL-4Rα) have been approved or are undergoing clinical trials, the development of inhalable mAbs targeting IL-4Rα presents significant challenges.

Objective

Capitalizing on the distinctive advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, we sought to develop a novel inhalable IL-4Rα Nb for effectively treating asthma.

Methods

Three IL-4Rα immunized Nb libraries were used to generate specific and functional IL-4Rα Nbs. LQ036, a bivalent Nb comprising 2 HuNb103 units, was constructed with a high affinity and specificity for human IL-4Rα. The efficacy, pharmacokinetics, and safety of inhaled LQ036 were evaluated in B-hIL4/hIL4RA humanized mice.

Results

LQ036 inhibited secreted embryonic alkaline phosphatase reporter activity, inhibited TF-1 cell proliferation, and suppressed phosphorylated signal transducer and activator of transduction 6 in T cells from patients with asthma. Crystal structure analysis revealed a binding region similar to dupilumab but with higher affinity, leading to better efficacy in blocking the signaling pathway. HuNb103 competed with IL-4 and IL-13 for IL-4Rα binding. Additionally, LQ036 significantly inhibited ovalbumin-specific IgE levels in serum, CCL17 levels in bronchoalveolar lavage fluid, bronchial mucous cell hyperplasia, and airway goblet cell hyperplasia in B-hIL4/hIL4RA humanized mice. Inhaled LQ036 exhibited favorable pharmacokinetics, safety, and tissue distribution, with higher concentrations observed in the lungs and bronchi.

Conclusions

These findings from preclinical studies establish the safety and efficacy of inhaled LQ036, underscoring its potential as a pioneering inhalable biologic therapy for asthma.

背景：可吸入生物制剂是提高哮喘治疗疗效和安全性的一种很有前景的方法。虽然一些针对 IL-4Rα 的单克隆抗体（mAbs）已获批准或正在进行临床试验，但针对 IL-4Rα 的可吸入 mAbs 的开发仍面临巨大挑战：利用纳米抗体（Nbs）在储存和给药过程中保持疗效的独特优势，我们试图开发一种新型可吸入的IL-4Rα Nb，以有效治疗哮喘：方法：利用三个IL-4Rα免疫Nb文库生成特异性和功能性IL-4Rα Nbs。LQ036是由两个HuNb103单元组成的二价Nb，对hIL-4Rα具有高亲和力和特异性。在 B-hIL4/hIL4Ra 人源化小鼠中评估了吸入 LQ036 的疗效、药代动力学和安全性：结果：LQ036能抑制哮喘患者T细胞中分泌型胚胎碱性磷酸酶（SEAP）报告活性、TF-1细胞增殖并抑制pSTAT6。晶体结构分析表明，HuNb103 的结合区域与 Dupilumab 相似，但具有更高的亲和力，因此在阻断信号通路方面具有更好的疗效。HuNb103与IL-4和IL-13竞争IL-4Rα的结合。此外，LQ036还能显著抑制B-hIL4/hIL4Ra人源化小鼠血清中的OVA特异性IgE水平、BALF中的CCL17水平、支气管粘液细胞增生和气道上皮细胞增生。吸入 LQ036 表现出良好的药代动力学、安全性和组织分布，在肺部和支气管中观察到较高的浓度：这些临床前研究结果证实了吸入式 LQ036 的安全性和有效性，凸显了它作为哮喘吸入式生物疗法先驱的潜力。

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引用次数: 0

News & Notes-AAAAI 新闻与说明-AAAAI

IF 11.4 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology

Pub Date : 2024-10-01 DOI: 10.1016/S0091-6749(24)00878-9

引用次数: 0

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