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.

使用650多名患有多种嗜酸性疾病的受试者的同类，从良性嗜酸性粒细胞嗜酸性症到嗜酸性白血病，我们继续识别和表征嗜酸性粒细胞菌患者的新型亚组，并表征嗜酸性症的患者，并探索对息肉症的靶向疗法的靶向疗法的反应，以增加对息护物的影响。我们还继续进行协作研究，研究了嗜酸性粒细胞在包括结核分枝杆菌在内的微生物感染反应中的作用，以及嗜酸性粒细胞在Covid-19的临床表现中的作用。随着影响嗜酸性粒细胞的治疗剂的数量，嗜酸性粒细胞迁移和嗜酸性粒细胞激活的增加，了解患有嗜酸性综合征性综合征的患者的驱动嗜酸性粒细胞和嗜酸性粒细胞激活的机制变得越来越重要。我们以前已经表明，HES的临床亚型是对常规和靶向疗法反应的重要预测指标（Kuang等人J Allergy Clin Immunol Archit 2018; Khoury等人J. J Allergy Clin Immunol练习2018）。这在嗜酸性粒细胞性肿瘤中可能最为明显，包括与Fip1l1 :: PDGFRA相关的肿瘤（Khoury等人，Allergy 2016）。早期靶向治疗的早期制度的主要障碍是市售诊断测试的不敏感性。回顾性分析我们的PDGFRA相关骨髓肿瘤患者的队列鉴定了39例使用荧光原位杂交（FISH）进行商业测试的患者，并使用NIH嵌套PCR进行了测试（Pongdee等人（Pongdee etal。ActaHeematologica 20223））。在20例FIP1L1 :: PCR阳性的患者中，有8名因鱼为阴性，导致伊马替尼治疗和不良临床结果的制度延迟。有针对性的疗法不仅为患者提供了新的选择，还可以深入了解嗜酸性粒细胞耗竭对人类的影响以及驱动嗜酸性粒细胞增多症和HES嗜酸性粒细胞激活的机制。正在进行的研究包括使用酪氨酸激酶抑制剂（伊马替尼和鲁糖尼替尼）用于治疗类固醇 - 抗耐药性HES，这是一项单一的地点研究，用于治疗情节性血管性水肿和嗜酸性粒细胞嗜酸性血管性血管性水肿和嗜酸性粒细胞增多症，这是一项多中心疗法的多中部试验，以研究HES的长期试验，以调查HES中的研究，以调查hES中的研究，以调查hES中的研究。和dex -pramipexole。我们先前已经描述了我们单一中心第二阶段安慰剂对照研究的苯珠单抗研究的结果，该研究证明了该药物在治疗 - frestractory pdgfra阴性HES患者中的功效，包括胃肠道受累的患者（Kuang etal。Kuangetal。N。N.N.N.N.Engl J Med 2019; Kuang etal。Jj j j jn。Jand。Jernergycinergy cincelunol练习2022222222222）。这些结果对HES中的链苯二甲珠单抗进行的一项正在进行的多中心3阶段研究和最近发表的苯二珠单抗研究的嗜酸性胃炎2阶段研究（Kliewer等人。柳叶刀胃肠道乙醇2023）发挥了作用。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嗜酸性粒细胞耗尽，但其他组织学特征和患者报告的症状并未得到显着改善。我们的小组最近开始探索性别，种族和种族对各种嗜酸性疾病的易感性和诊断的作用。 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伊马替尼治疗之前的肿瘤和来自同一患者的外周血液单核细胞，以识别可能解释这种疾病中极端男性占主导地位的遗传特征（Rheinbay等人的血液进展2023）。尽管没有发现明显的遗传特征，但这项研究表明，PDGFR重新培养的HES具有简单的基因组学，可以解释伊马替尼治疗几乎普遍持续的缓解。我们还开始研究导致嗜酸性粒细胞性胃肠道疾病流行病学明显差异的因素（Sabet等人J Allergy Clin Immunol练习2021年，Chehade等人Chehade等。从历史上看，嗜酸性粒细胞被视为对蠕虫感染和过敏原反应中主要作用的效应细胞。与此一致，我们小组的最新研究集中在嗜酸性粒细胞和嗜酸性粒细胞激活在丝虫病中的临床表现和治疗后反应中的作用（Herrick等人Clin Infect DIS 2020; Legrand等人Clin Infect DIS DIS DIS DIS 2017; Legrand etal。Legrandet al。Clin。Clin。Clin。Clin。Infect DIS 20211）。然而，在过去的十年中，人们对嗜酸性粒细胞在调节对非顽固病原体的反应中的作用一直在增加。为了解决这个问题，我们与Katrin Mayer-Barber博士进行了合作，以检查嗜酸性粒细胞在宿主免疫反应中对肺部感染的免疫反应的作用，该反应与结核分枝杆菌（MTB）以及最近的SARS-COV2。迄今为止，我们的数据表明，嗜酸性粒细胞在感染的头几周内以与CCR3无关的GPR183依赖性方式招募到肺部（Bohrer等人的细胞REP 2022），并且这些肺嗜酸性嗜酸盐可能在策划早期的肺肺含量20 expection e Allate Innate Innate Reverse（Buhr ext）中（BOHREN）的关键作用。在鼠模型和人类中正在进行的研究表明，肺嗜酸性粒细胞也是COVID-19感染的特征，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）

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

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

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

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