Eosinophils and Eosinophil Activation in the Pathogenesis of Human Disease

人类疾病发病机制中的嗜酸性粒细胞和嗜酸性粒细胞激活

基本信息

批准号：
10927855
负责人：
Amy Klion
金额：
$ 192.27万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927855
关键词：
2019-nCoV Address Affect Aftercare Allergens Allergic Angioneurotic Edema Automobile Driving Barbering Benign Blood COVID-19 Cells Chromosome 4 Clinical Collaborations Data Diagnosis Diagnostic tests Disease Disease remission Disseminated eosinophilic collagen disease Effector Cell Eosinophilia Eosinophilic Gastritis Eosinophilic Gastrointestinal Disease Eosinophilic leukemia Epidemiology Ethnic Origin Filariasis Fluorescent in Situ Hybridization Follow-Up Studies Gastric Tissue Genetic Genomics Goals Histologic Homeostasis Human Hypersensitivity Imatinib Immune response Infection Innate Immune Response Institution Location Longterm Follow-up Lung Lung infections Molecular Abnormality Mycobacterium tuberculosis Myeloproliferative disease Nested PCR Organ Outcome PDGFRA gene PDGFRB gene Pathogenesis Patients Peripheral Blood Eosinophilia Peripheral Blood Mononuclear Cell Phase Play Predisposition Publishing Pulmonary Eosinophilia Race Rare Diseases Reaction Refractory Reporting Role SARS-CoV-2 infection Site Steroids Symptoms Testing Therapeutic Agents Tuberculosis Tumor Suppressor Proteins Tyrosine Kinase Inhibitor United States National Institutes of Health X Chromosome clinical subtypes cohort conventional therapy diagnostic tool eosinophil gastrointestinal genome sequencing helminth infection human disease improved insight interest investigator-initiated trial male mepolizumab microbial migration mouse model neoplastic novel novel diagnostics participant enrollment pathogen patient subsets phase 2 study phase 3 study phase III trial placebo controlled study predicting response recruit response sex targeted treatment whole genome

项目摘要

Using a cohort of more than 650 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to identify and characterize novel subgroups of patients with eosinophilia and to explore responses to targeted therapies with the goal of increasing our understanding of the role of eosinophils in homeostasis and disease pathogenesis. We have also continued our collaborative studies examining the role of eosinophils in the immune response to microbial infections, including M. tuberculosis, and the role of eosinophils in the clinical manifestations of COVID-19. As the number of therapeutic agents that affect eosinophils, eosinophil migration and eosinophil activation increase, it is becoming increasingly important to understand the mechanisms driving eosinophilia and eosinophil activation in patients presenting with hypereosinophilic syndromes. We have previously shown that the clinical subtype of HES is an important predictor of response to conventional and targeted therapies (Kuang et al. J Allergy Clin Immunol Pract 2018; Khoury et al. J Allergy Clin Immunol Pract 2018). This is perhaps most evident in eosinophilic myeloid neoplasms, including those associated with FIP1L1::PDGFRA (Khoury et al. Allergy 2016). A major obstacle to early institution of targeted therapy is the insensitivity of commercially available diagnostic tests. Retrospective analysis of our cohort of patients with PDGFRA-associated myeloid neoplasms identified 39 patients with who had undergone commercial testing using fluorescence in situ hybridization (FISH) as well as testing using nested PCR at NIH (Pongdee et al. Acta Haematologica 2023). Eight of the 20 patients positive for FIP1L1::PDFGRA by PCR were negative by FISH, resulting in a significant delay in institution of imatinib therapy and adverse clinical outcomes. Targeted therapies not only provide new options for patients but provide insight into the effects of eosinophil depletion in humans and the mechanisms driving eosinophilia and eosinophil activation in HES. Ongoing studies include the use of tyrosine kinase inhibitors (imatinib and ruxolitinib) for the treatment of steroid-refractory HES, a single site study of mepolizumab for the treatment of episodic angioedema and eosinophilia, a multicenter phase 3 trial of benralizumab for HES, as well as long-term followup studies of HES patients enrolled on investigator-initiated trials of benralizumab and dexpramipexole. We have previously described the results of our single center phase 2 placebo-controlled study of benralizumab that demonstrated efficacy of this agent in patients with treatment-refractory PDGFRA-negative HES, including patients with gastrointestinal involvement (Kuang et al. N Engl J Med 2019; Kuang et al. J Allergy Clin Immunol Pract 2022). These results were instrumental in the initiation of an ongoing multicenter phase 3 study of benralizumab in HES and a recently published phase 2 study of benralizumab for eosinophilic gastritis (Kliewer et al. Lancet Gastroenterol Hepatol 2023). Whereas eosinophils were depleted in the blood and gastric tissue in most of the patients in this small placebo-controlled study, other histologic features and patient-reported symptoms were not significantly improved. Our group has recently begun to explore the roles of sex, race, and ethnicity on susceptibility to and diagnosis of varied eosinophilic disorders. PDGFR-associated myeloid neoplasms show an extreme male predominance (Klion et al. Blood 2003) despite the location of the genetic abnormality on chromosome 4. Since tumor suppressors on the X chromosome have been shown to influence sex predominance in other neoplastic disorders, we performed whole genome sequencing on eosinophils from 11 patients with PDGFR-associated myeloid neoplasms prior to imatinib therapy and on peripheral blood mononuclear cells from the same patients in durable remission to identify genetic features that might explain the extreme male predominance in this disorder (Rheinbay et al. Blood Advances 2023). Although no obvious genetic feature was identified, this study showed that PDGFR-rearranged HES has simple genomics that could explain the nearly universal sustained remission with imatinib therapy. We are also beginning to examine factors that contribute to apparent differences in the epidemiology of eosinophilic gastrointestinal disorders (Sabet et al. J Allergy Clin Immunol Pract 2021, Chehade et al. Therapeut Adv Rare Dis 2023). Historically, eosinophils have been viewed as effector cells with primary roles in the response to helminth infection and allergens. Consistent with this, recent studies in our group have focused on the role of eosinophils and eosinophil activation in the clinical manifestations and post-treatment reactions in filariasis (Herrick et al. Clin Infect Dis 2020; Legrand et al. Clin Infect Dis 2017; Legrand et al. Clin Infect Dis 2021). Over the past decade, however, there has been increasing interest in the role of eosinophils in the modulation of responses to non-helminth pathogens. To address this issue, we initiated a collaboration with Dr. Katrin Mayer-Barber to examine the role of eosinophils in the host immune response to pulmonary infection with Mycobacterium tuberculosis (Mtb) and, more recently, SARS-CoV2. To date, our data has demonstrated that eosinophils are recruited to the lungs within the first few weeks of infection in a CCR3-independent, GPR183-dependent manner (Bohrer et al. Cell Rep 2022) and that these pulmonary eosinophils may play a key role in orchestrating the early pulmonary innate immune response after Mtb infection (Bohrer et al. J Exp Med 2021). Ongoing studies in murine models and in humans suggest that pulmonary eosinophilia is also a feature of COVID-19 infection but that recruitment occurs via a different mechanism.

通过使用 650 多名患有各种嗜酸性粒细胞疾病（从良性嗜酸性粒细胞增多症到嗜酸性粒细胞白血病）的受试者队列，我们继续识别和表征新的嗜酸性粒细胞增多症患者亚组，并探索对靶向治疗的反应，目的是提高我们的治疗效果。了解嗜酸性粒细胞在体内平衡和疾病发病机制中的作用。我们还继续开展合作研究，探讨嗜酸性粒细胞在微生物感染（包括结核分枝杆菌）免疫反应中的作用，以及嗜酸性粒细胞在 COVID-19 临床表现中的作用。随着影响嗜酸性粒细胞、嗜酸性粒细胞迁移和嗜酸性粒细胞活化的治疗药物数量的增加，了解嗜酸性粒细胞增多综合征患者中嗜酸性粒细胞增多和嗜酸性粒细胞活化的驱动机制变得越来越重要。我们之前已经证明，HES 的临床亚型是对常规和靶向治疗反应的重要预测因子（Kuang 等人，J Allergy Clin Nutritional Pract 2018；Khoury 等人，J Allergy Clin Nutritional Pract 2018）。这可能在嗜酸性粒细胞肿瘤中最为明显，包括与 FIP1L1::PDGFRA 相关的肿瘤（Khoury 等人，Allergy 2016）。早期开展靶向治疗的一个主要障碍是商业诊断测试的不敏感性。我们对 PDGFRA 相关骨髓肿瘤患者队列进行回顾性分析，确定了 39 名患者接受过荧光原位杂交 (FISH) 商业检测以及 NIH 巢式 PCR 检测（Pongdee 等人 Acta Haematologica 2023）。 20 名 FIP1L1::PDFGRA PCR 呈阳性的患者中有 8 名 FISH 呈阴性，导致伊马替尼治疗的实施显着延迟并导致不良临床结果。靶向治疗不仅为患者提供了新的选择，而且还提供了对人类嗜酸性粒细胞耗竭的影响以及 HES 中嗜酸性粒细胞增多和嗜酸性粒细胞激活的驱动机制的深入了解。正在进行的研究包括使用酪氨酸激酶抑制剂（伊马替尼和鲁索替尼）治疗类固醇难治性 HES、美泊利单抗治疗阵发性血管性水肿和嗜酸性粒细胞增多症的单中心研究、贝那利珠单抗治疗 HES 的多中心 3 期试验以及作为对参加研究者发起的贝那利珠单抗试验的 HES 患者的长期随访研究右旋普拉克索。我们之前已经描述了贝那利珠单抗的单中心 2 期安慰剂对照研究的结果，该研究证明了该药物对难治性 PDGFRA 阴性 HES 患者（包括胃肠道受累患者）的疗效（Kuang 等人，N Engl J Med 2019） Kuang 等人，《过敏临床免疫实践杂志》2022 年。这些结果有助于启动正在进行的贝那利珠单抗治疗 HES 的多中心 3 期研究以及最近发表的贝那利珠单抗治疗嗜酸性胃炎的 2 期研究（Kliewer 等人，Lancet Gastroenterol Hepatol 2023）。尽管在这项小型安慰剂对照研究中，大多数患者的血液和胃组织中的嗜酸性粒细胞被耗尽，但其他组织学特征和患者报告的症状并未显着改善。我们的小组最近开始探索性别、种族和民族对各种嗜酸性粒细胞疾病的易感性和诊断的作用。尽管遗传异常位于 4 号染色体上，PDGFR 相关的骨髓肿瘤仍表现出极端的男性优势（Klion 等人 Blood 2003）。由于 X 染色体上的肿瘤抑制因子已被证明会影响其他肿瘤疾病的性别优势，因此我们进行了对伊马替尼治疗前 11 名 PDGFR 相关骨髓肿瘤患者的嗜酸性粒细胞以及同一患者的外周血单核细胞进行全基因组测序在持久缓解中，以确定可能解释这种疾病中男性极端主导的遗传特征（Rheinbay et al. Blood Advances 2023）。虽然没有发现明显的遗传特征，但这项研究表明 PDGFR 重排的 HES 具有简单的基因组学，可以解释伊马替尼治疗几乎普遍的持续缓解。我们还开始研究导致嗜酸性粒细胞胃肠道疾病流行病学明显差异的因素（Sabet 等人 J Allergy Clin Immunol Pract 2021，Chehade 等人 Therapeut Adv Rare Dis 2023）。从历史上看，嗜酸性粒细胞一直被视为在响应蠕虫感染和过敏原中起主要作用的效应细胞。与此相一致的是，我们小组最近的研究重点是嗜酸性粒细胞和嗜酸性粒细胞活化在丝虫病临床表现和治疗后反应中的作用（Herrick et al. Clin Infect Dis 2020；Legrand et al. Clin Infect Dis 2017；Legrand等人，临床感染疾病 2021）。然而，在过去的十年中，人们对嗜酸性粒细胞在调节非蠕虫病原体反应中的作用越来越感兴趣。为了解决这个问题，我们与 Katrin Mayer-Barber 博士展开合作，研究嗜酸性粒细胞在宿主对结核分枝杆菌 (Mtb) 以及最近的 SARS-CoV2 肺部感染的免疫反应中的作用。迄今为止，我们的数据表明，嗜酸性粒细胞在感染的最初几周内以不依赖 CCR3、依赖 GPR183 的方式被招募到肺部（Bohrer 等人，Cell Rep 2022），并且这些肺部嗜酸性粒细胞可能发挥关键作用协调 Mtb 感染后的早期肺部先天免疫反应（Bohrer 等人，J Exp Med 2021）。正在进行的小鼠模型和人类研究表明，肺嗜酸性粒细胞增多也是 COVID-19 感染的一个特征，但招募是通过不同的机制发生的。

项目成果

期刊论文数量（69）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Eosinophilia: introduction.

嗜酸性粒细胞增多症：简介。

DOI：
10.1053/j.seminhematol.2012.01.004
发表时间：
2012
期刊：
Seminars in hematology
影响因子：
3.6
作者：
Klion,AmyD
通讯作者：
Klion,AmyD

A Randomized, Placebo-controlled, Double-blind Pilot Study of Single-dose Humanized Anti-IL5 Antibody (Reslizumab) for the Reduction of Eosinophilia Following Diethylcarbamazine Treatment of Loa loa Infection.

单剂量人源化抗 IL5 抗体 (Reslizumab) 用于减少二乙基卡马嗪治疗 Loa loa 感染后嗜酸性粒细胞增多的随机、安慰剂对照、双盲初步研究。

DOI：
10.1093/cid/ciaa1365
发表时间：
2021
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
0
作者：
Legrand,Fanny;Herrick,Jesica;Makiya,Michelle;Ramanathan,Roshan;Thompson,Reagan;Rampertaap,Shakuntala;Stoddard,Jennifer;Ware,JeanAnne;Fay,MichaelP;Holland-Thomas,Nicole;Nutman,ThomasB;Klion,AmyD
通讯作者：
Klion,AmyD

Swiss cheese heart.

瑞士奶酪心。

DOI：
10.1093/eurheartj/ehx626
发表时间：
2018
期刊：
European heart journal
影响因子：
39.3
作者：
Groves,DanielW;Klion,AmyD;Chen,MarcusY;Arai,AndrewE
通讯作者：
Arai,AndrewE

Surgical management of adult endocardial fibroelastosis.

DOI：
10.1016/j.jtcvs.2017.05.050
发表时间：
2017-11
期刊：
The Journal of thoracic and cardiovascular surgery
影响因子：
0
作者：
Chan JL;Rosing DR;Klion AD;Horvath KA
通讯作者：
Horvath KA

Platelet-derived growth factor receptor-alpha-positive myeloid neoplasm presenting as eosinophilic gastrointestinal disease.

DOI：
10.1016/j.jaip.2020.01.055
发表时间：
2020-06
期刊：
The journal of allergy and clinical immunology. In practice
影响因子：
0
作者：
Constantine GM;Ware J;Brown T;Thumm L;Kamal N;Kumar S;Kleiner D;Maric I;Klion AD
通讯作者：
Klion AD