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

• 批准号: 8745553
• 负责人: Amy Klion
• 金额: $ 100.42万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 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/8745553
• 关键词: 14 year old; Acute; Adrenal gland hypofunction; Adverse effects; Aftercare; Antibodies; Ascaridil; Benign; Blood; Bone Marrow; Cessation of life; Characteristics; Chronic; Classification; Clinical; Clinical Immunology; Clinical Protocols; Comparative Study; Data; Dermatologic; Development; Diethylcarbamazine; Disease; Disseminated eosinophilic collagen disease; Dose; Double-Blind Method; Drug Hypersensitivity; Enrollment; Eosinophilia; Eosinophilic leukemia; Epstein-Barr Virus Infections; Evaluation; Extrinsic asthma; Family; Glucocorticoids; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Helminths; Hematopoietic Stem Cell Transplantation; Homeostasis; Human Herpesvirus 4; Hypersensitivity; IgE; Imatinib; Infection; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Interleukin-9; Ivermectin; Loa; Loa loa; Loiasis; Methods; Microfilaria; Monoclonal Antibodies; Onchocerciasis; PDGFRA gene; Parasitic infection; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Population; Predisposing Factor; Prednisone; Prevalence; Production; Prospective Studies; Reaction; Reporting; Resistance; Risk; Role; Serum; Serum Markers; Severe Adverse Event; Skin; Subgroup; Surface; T-Lymphocyte; Therapeutic; Time; Tissues; Toxic effect; Tyrosine Kinase Inhibitor; United States National Institutes of Health; cohort; cytokine; eosinophil; human SIGLEC8 protein; human disease; mepolizumab; neoplastic; neutralizing antibody; novel; novel diagnostics; outcome forecast; peripheral blood; placebo controlled study; prevent; response; screening; tool; viral DNA

Using a cohort of more than 300 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. Although most classifications of HES allude to a group of patients with absolute eosinophil count (AEC) >1500/mm3 in the absence of clinical manifestations (hypereosinophilia of unknown significance or HEUS), little is known about the characteristics and long-term prognosis of such patients in the absence of therapy. Among the 210 subjects >14 years of age with unexplained AEC >1500/mm3 evaluated at the NIH between January 1991 and December 2011, 36 were PDGFRA-negative and on no therapy at the time of evaluation. Of these, 8 (22%) were asymptomatic and remained eosinophilic (peak AEC 1856-7170/mm3) and without clinical manifestations of eosinophilia on no therapy for > 5 years (range 7-29 years). Peak eosinophil counts, surface expression of eosinophil activation markers, serum levels of IL-5, GM-CSF, IL-9, and IL-17A, and the prevalence of aberrant or clonal T cell populations were similar in the subjects with HEUS and untreated subjects with PDGFRAnegative HES (n=28). Interestingly, serum levels of IgE and IL-13 were significantly increased only in subjects with HES. Whereas these data suggest that completely asymptomatic patients with eosinophilia >1500/mm3 can be followed closely without specific treatment, a multicenter prospective study is planned to better assess the risk of and predisposing factors for progression to HES in patients with HEUS (Chen et al. 2013 J Allergy Clinical Immunology, in press). LHES is a rare eosinophilic disorder of unknown cause in which production of cytokines by clonal/and or aberrant T lymphocytes drives blood and tissue eosinophilia. We reported a case of LHES with dramatic dermatologic manifestations caused by an Epstein-Barr virus (EBV)-infected T cell clone producing eosinophilopoietic cytokines (IL-4, IL-5, and IL-13) (Klion et al. Blood 2013). EBV DNA was demonstrated in T cells in the peripheral blood (peak level 3.97 million copies/ml blood), skin and bone marrow using FISH and PCR, consistent with chronic active EBV infection (CAEBV). Elevated EBV DNA levels (11,800 copies/ml blood) were found in one additional patient with LHES and dermatologic disease (of 15 studied). Although these data suggest that CAEBV is not a common cause of LHES, EBV screening of patients with LHES and a demonstrable T cell clone should be performed to identify patients with CAEBV who may benefit from early consideration for hematopoietic stem cell transplantation. Other novel subgroups of eosinophilic subjects currently under study include a family with autosomal dominant eosinophilia and a cohort of subjects with cyclic eosinophilia. We have also initiated a new clinical protocol to determine whether the acute response to a single dose of prednisone can predict the dose ultimately needed to control eosinophilia and clinical manifestations of HES and to explore the mechanisms of glucocorticoid resistance in HES. The effects of novel therapies for the treatment of hypereosinophilic syndromes, including monoclonal antibodies to IL-5 and the tyrosine kinase inhibitor, imatinib, remain a primary focus. Long-term (5 year) followup of subjects enrolled on a placebo-controlled study of the anti-IL-5 antibody, mepolizumab was completed. The drug continued to show excellent efficacy in the majority of subjects and was not associated with toxicity or the development of neutralizing antibodies (Roufosse et al. 2012 J Allergy Clin Immunol). We have also begun to explore the therapeutic potential of antibodies against several additional novel targets, including EMR1 (Legrand J et al. Allergy Clin Immunol, in revision) and siglec-8 (Na et al. 2012 J Immunol Methods). Treatment of the filarial infection loiasis with diethylcarbamazine (DEC) can be associated with severe adverse events, including death, that are associated with a dramatic rise in eosinophilia and are positively correlated with the number of circulating microfilariae in the blood. In the past year, we have expanded our studies of monoclonal antibodies targeting IL-5 to explore the role of eosinophilia in post-treatment reactions following DEC treatment of loiasis. A double-blind, placebo-controlled study of the anti-IL-5 antibody, reslizumab, to prevent post-treatment side effects of DEC in patients with Loa loa infection is currently underway. Because similar side effects have been seen in Loa infected patients during mass administration of ivermectin for onchocerciasis control, we conducted a comparative study of post-treatment reactions following single dose ivermectin or single dose DEC. Of note, despite comparable side effect profiles, the patterns of post-treatment eosinophilia were dramatically different between the two groups. Analysis of cytokines and eosinophil activation markers is currently underway.

通过使用 300 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。 尽管 HES 的大多数分类都涉及一组在没有临床表现（意义不明的嗜酸性粒细胞增多症或 HEUS）的情况下绝对嗜酸性粒细胞计数 (AEC) >1500/mm3 的患者，但人们对此类患者的特征和长期预后知之甚少。患者在没有接受治疗的情况下。 1991 年 1 月至 2011 年 12 月期间，在 NIH 评估的 210 名年龄 >14 岁、不明原因 AEC >1500/mm3 的受试者中，36 名受试者为 PDGFRA 阴性，且在评估时未接受任何治疗。其中，8 例 (22%) 无症状，仍保持嗜酸性粒细胞增多（峰值 AEC 1856-7170/mm3），并且在未接受治疗超过 5 年（范围 7-29 年）后没有出现嗜酸性粒细胞增多的临床表现。 HEUS 和未治疗受试者的嗜酸性粒细胞峰值计数、嗜酸性粒细胞活化标记物的表面表达、IL-5、GM-CSF、IL-9 和 IL-17A 的血清水平以及异常或克隆 T 细胞群的患病率相似PDGFRA 阴性 HES 受试者 (n=28)。有趣的是，只有 HES 受试者的血清 IgE 和 IL-13 水平显着升高。尽管这些数据表明嗜酸粒细胞增多>1500/mm3的完全无症状患者无需特殊治疗即可密切随访，但计划进行一项多中心前瞻性研究以更好地评估HEUS患者进展为HES的风险和诱发因素（Chen等，2017）。 2013 年过敏临床免疫学杂志，正在出版）。 LHES 是一种原因不明的罕见嗜酸性粒细胞疾病，其中克隆/和/或异常 T 淋巴细胞产生细胞因子导致血液和组织嗜酸性粒细胞增多。我们报道了一例 LHES 病例，该病例由 Epstein-Barr 病毒 (EBV) 感染的 T 细胞克隆产生嗜酸性细胞因子（IL-4、IL-5 和 IL-13）引起，具有显着的皮肤病学表现（Klion 等人 Blood 2013） 。使用 FISH 和 PCR 证明外周血（峰值水平为 397 万拷贝/ml 血液）、皮肤和骨髓中的 T 细胞中存在 EBV DNA，这与慢性活动性 EBV 感染 (CAEBV) 一致。在另外一名患有 LHES 和皮肤病的患者（研究的 15 名患者）中发现了 EBV DNA 水平升高（11,800 拷贝/ml 血液）。尽管这些数据表明 CAEBV 不是 LHES 的常见原因，但应对 LHES 和可证明的 T 细胞克隆患者进行 EBV 筛查，以确定可能受益于早期考虑造血干细胞移植的 CAEBV 患者。 目前正在研究的其他新的嗜酸性粒细胞受试者亚组包括常染色体显性嗜酸性粒细胞增多症家族和周期性嗜酸性粒细胞增多症受试者队列。 我们还启动了一项新的临床方案，以确定对单剂量泼尼松的急性反应是否可以预测控制嗜酸性粒细胞增多和 HES 临床表现最终所需的剂量，并探索 HES 糖皮质激素耐药的机制。 治疗嗜酸性粒细胞增多综合征的新疗法（包括 IL-5 单克隆抗体和酪氨酸激酶抑制剂伊马替尼）的效果仍然是主要关注点。 参加抗 IL-5 抗体美泊利单抗安慰剂对照研究的受试者的长期（5 年）随访已完成。该药物在大多数受试者中继续显示出优异的疗效，并且与毒性或中和抗体的产生无关（Roufosse 等人，2012 J Allergy Clin Immunol）。 我们还开始探索针对其他几个新靶标的抗体的治疗潜力，包括 EMR1（Legrand J 等人，Allergy Clin Immunol，修订中）和 siglec-8（Na 等人，2012 J 免疫学方法）。 使用二乙基卡马嗪 (DEC) 治疗丝虫感染罗阿病可能会导致严重的不良事件，包括死亡，这些不良事件与嗜酸性粒细胞增多有关，并且与血液中循环微丝蚴的数量呈正相关。在过去的一年中，我们扩大了针对 IL-5 的单克隆抗体的研究，以探讨嗜酸性粒细胞增多在罗阿西病 DEC 治疗后反应中的作用。目前正在进行一项抗 IL-5 抗体 reslizumab 的双盲、安慰剂对照研究，该研究旨在预防 Loa loa 感染患者接受 DEC 治疗后的副作用。由于在大规模施用伊维菌素控制盘尾丝虫病期间，在 Loa 感染患者中也发现了类似的副作用，因此我们对单剂量伊维菌素或单剂量 DEC 后的治疗后反应进行了比较研究。值得注意的是，尽管副作用相似，但两组治疗后嗜酸性粒细胞增多的模式却截然不同。 目前正在进行细胞因子和嗜酸性粒细胞活化标记物的分析。