Th1/Th17 Immune Regulation in Severe Allergic Asthma

严重过敏性哮喘中的 Th1/Th17 免疫调节

基本信息

批准号：
10348780
负责人：
AMIT K MITRA
金额：
$ 7.45万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348780
关键词：
Aconitic Acid Acute Address Adoptive Transfer Affect Age Airway Disease Allergens Allergic Allergic inflammation Anti-Inflammatory Agents Antigen-Antibody Complex Antiinflammatory Effect Asthma CD4 Positive T Lymphocytes Cell physiology Cells Chronic Clinical Coupled Cues Data Dendritic Cells Development Disease Economic Burden Effector Cell Equilibrium Esters Experimental Models Exposure to Extrinsic asthma Foundations Fumarates Genes Goals Grant Health Health Care Costs Health Status Hyperactivity Immune Immune response Immunity Impairment Infection Infiltration Inflammation Inflammatory Response Knockout Mice Knowledge Lung Lung infections Maintenance Mass Spectrum Analysis Measures Mediastinal lymph node group Mediating Metabolic Mitochondria Molecular Morbidity - disease rate Neutrophil Infiltration Outcome Pathologic Pathway interactions Persons Phase Phenotype Play Population Prevention Process Production Property Public Health Pyroglyphidae Regulation Reporting Research Resolution Respiration Respiratory Tract Infections Risk Risk Factors Role Signal Transduction Steroid Resistance Steroid-resistant asthma Stimulator of Interferon Genes T-Lymphocyte Testing Th2 Cells Therapeutic Therapeutic Intervention Translating Treatment Efficacy Viral Respiratory Tract Infection adaptive immune response airborne allergen airway immune response airway inflammation asthma exacerbation asthmatic asthmatic airway base cell mediated immune response cell motility chronic inflammatory disease clinically relevant effector T cell eosinophil expectation genetic signature granulocyte immune activation immunoregulation improved in vivo inflammatory milieu innovation metabolomics mouse model neutrophil novel novel therapeutic intervention prevent reduce symptoms response sensor therapeutic evaluation transcriptome translatable strategy

项目摘要

Project Summary/Abstract This is the resubmission of a grant entitled “Th1/Th17 Immune Regulation in Severe Allergic Asthma” (1 RO3 AI163794-01) which focuses on the mechanism of dendritic cell (DCs)-mediated regulation of Th1/Th17 immune response in neutrophilic airway inflammation. The overall goal of the resubmission application is to gain new knowledge about how metabolic reprograming of DCs contribute to immune priming and immune-polarizing effector function(s) and how it predisposes and generate the inflammatory milieu in severe asthmatic airways. We know from clinical and experimental evidence that respiratory infections, which are a common trigger for asthma exacerbations and contribute to severe form of the disease, manifested a mixed granulocytic airway inflammation comprising both neutrophils and eosinophils. Moreover, we believe that asthma exacerbations in presence of infections leads to stimulate innate sensor STING (stimulator of interferon genes) pathways, as well as skewing Th1/Th17 immune response in the airways. We recently reported that not only activation and immune-priming function of DCs are coupled to profound alterations of the cellular metabolic state, but also it comprises a DC-specific response modulated by the endogenous key metabolites (Jaiswal et al., Immun. Inflamm. Dis, 2019). New and exciting preliminary data reveal that DC-specific increase of immune responsive gene1 (Irg1), which decarboxylate cis-aconitate to produce immunoregulatory metabolite itaconate, in Th1/Th17 asthmatic lung relative to naïve controls presumably to help resolve airway inflammation. This induction of Irg1 is coupled with itaconate productions in DCs with house dust mite (HDM) and STING stimulations. Results show that exogenous itaconate treatment restored mitochondrial respiration and the capacity of DCs to polarize CD4+ T cells, suggesting an immunoregulatory role of itaconate on DCs immune-priming function(s). The anti- inflammatory effect of itaconate was translated in vivo, where adoptive transfer of itaconate treated DCs reduced airway inflammation and T cell-mediated immune response relative to vehicle-treated DCs. From these pieces of evidence we hypothesize that itaconate plays a distinct regulatory role in lung DCs and can be induced to limit neutrophilic airway inflammation. To test this hypothesis, in Aim1, we will first determine if endogenous itaconate is required for developing airway inflammation and Th1/Th17 immune response using Irg1 knockout mice. In Aim2, we will determine whether exogenous treatment of the itaconate derivative exerts potential anti- inflammatory properties in vivo. Taken together, these studies will expand on the limited knowledge of how Irg1/itaconate axis regulates DC effector function and whether therapeutic interventions targeting the airways could reduce or abolish Th1/Th17 immune response in severe asthma.

项目概要/摘要这是重新提交题为“严重过敏性哮喘中的 Th1/Th17 免疫调节”的拨款 (1 RO3 AI163794-01) 重点研究树突状细胞 (DC) 介导的 Th1/Th17 免疫调节机制中性粒细胞性气道炎症反应重新提交申请的总体目标是获得新的结果。关于树突状细胞的代谢重编程如何促进免疫启动和免疫极化的知识效应器功能及其如何在严重哮喘气道中诱发和产生炎症环境。我们从临床和实验证据中得知，呼吸道感染是导致呼吸道感染的常见诱因。哮喘恶化并导致疾病的严重形式，表现为混合粒细胞气道此外，我们认为哮喘会加重。感染的存在也会刺激先天传感器 STING（干扰素基因刺激剂）通路我们最近报道，不仅激活了气道中的 Th1/Th17 免疫反应，而且还导致了 Th17 免疫反应的扭曲。 DC 的免疫启动功能与细胞代谢状态的深刻改变有关，而且它也包括由内源性关键代谢物调节的 DC 特异性反应（Jaiswal 等人，Immun. Inflamm.Dis，2019）。新的令人兴奋的初步数据表明 DC 特异性的免疫反应增加。 Th1/Th17 中的基因 1 (Irg1)，使顺乌头酸脱羧产生免疫调节代谢物衣康酸与初始对照相比，哮喘肺可能有助于解决 Irg1 的这种诱导。结果显示，DC 中衣康酸的产生与屋尘螨 (HDM) 和 STING 刺激相结合。外源衣康酸治疗恢复了线粒体呼吸和 DC 极化 CD4+ 的能力 T 细胞，表明衣康酸对 DC 免疫启动功能具有免疫调节作用。衣康酸的炎症作用在体内转化，衣康酸处理的树突状细胞的过继转移减少气道炎症和 T 细胞介导的对载体处理的 DC 的免疫相关反应。我们追寻的大量证据表明，衣康酸在肺 DC 中发挥着独特的调节作用，并且可以诱导限制为了检验这一假设，在 Aim1 中，我们首先确定是否存在内源性衣康酸。使用 Irg1 敲除小鼠产生气道炎症和 Th1/Th17 免疫反应是必需的。目标2，我们将确定衣康酸衍生物的外源治疗是否发挥潜在的抗- 总的来说，这些研究将扩展关于体内炎症特性的有限知识。 Irg1/衣康酸轴调节 DC 效应器功能以及是否针对气道进行治疗干预可以减少或消除严重哮喘患者的 Th1/Th17 免疫反应。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of OX40 agonists for canine cancer immunotherapy.

开发用于犬癌症免疫治疗的 OX40 激动剂。

DOI：
发表时间：
2022-10-21
期刊：
影响因子：
5.8
作者：
Ruiz, Damien;Haynes, Chloe;Marable, Jonathan;Pundkar, Chetan;Nance, Rebecca L;Bedi, Deepa;Agarwal, Payal;Suryawanshi, Amol S;Mishra, Amarjit;Smith, Bruce F;Sandey, Maninder
通讯作者：
Sandey, Maninder

Role of IL-27 in HSV-1-Induced Herpetic Stromal Keratitis.

IL-27 在 HSV-1 诱导的疱疹性基质角膜炎中的作用。

DOI：
发表时间：
2023-08-01
期刊：
影响因子：
0
作者：
Antony, Ferrin;Pundkar, Chetan;Sandey, Maninder;Mishra, Amarjit;Suryawanshi, Amol
通讯作者：
Suryawanshi, Amol

Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging.

短腭、肺和鼻上皮克隆 1 (SPLUNC1) 水平决定衰老过程中类固醇抵抗性气道炎症。

DOI：
发表时间：
2022-01-01
期刊：
影响因子：
0
作者：
Jaiswal, Anil Kumar;Yadav, Jyoti;Makhija, Sangeet;Sandey, Maninder;Suryawanshi, Amol;Mitra, Amit Kumar;Mishra, Amarjit
通讯作者：
Mishra, Amarjit