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：
8336339
负责人：
Amy Klion
金额：
$ 85.07万
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/8336339
关键词：
5q31 Adrenal gland hypofunction Adverse effects Affect Aftercare Angioneurotic Edema Antibodies Benign Blood Platelets Candidate Disease Gene Clinical Clinical Research Collaborations Cyclic Neutropenia DNA Development Disease Disease Marker Disseminated eosinophilic collagen disease Drug Hypersensitivity Enrollment Eosinophilia Eosinophilic leukemia Eotaxin Extrinsic asthma Family Family member Genes Goals Granulocyte-Macrophage Colony-Stimulating Factor Helminths Homeostasis Imatinib Infection Interleukin-13 Interleukin-5 Loa loa Loiasis Maps Monoclonal Antibodies Multicenter Studies Mutation Parasitic infection Pathogenesis Patients Periodicity Pharmaceutical Preparations Reaction Refractory Regulation Role Serum Subgroup Surface Symptoms Systemic Mastocytosis Therapeutic Agents Tissues Toxic effect Tryptase Tyrosine Kinase Inhibitor Variant cohort cytokine eosinophil genome sequencing human disease in vivo inflammatory marker mastocytosis mepolizumab neoplastic neutralizing antibody neutrophil novel novel diagnostics novel marker novel therapeutic intervention peripheral blood placebo controlled study receptor tool

项目摘要

Using a cohort of more than 250 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to look for new markers that distinguish between variants of hypereosinophilic syndrome. Assessment of serum and surface IL-5 receptor levels in a large cohort of patients with eosinophilia and/or mastocytosis suggests that regulation of this receptor occurs in vivo. Serum levels of the receptor were correlated with eosinophilia, serum levels of IL-5 and IL-13 and markers of eosinophil activation. Interestingly, serum receptor levels were also elevated in patients with systemic mastocytosis without eosinophilia and correlated with both serum tryptase and surface markers of eosinophil activation. These findings may have important implications in the setting of recently developed therapeutic agents targeting IL-5 and its receptor. We have previously described a family with an autosomal dominant variant of hypereosinophilic syndrome that maps to chromosome 5q31-33. Exhaustive attempts to identify the gene responsible for this condition, including candidate gene sequencing, array CGHY, expression analysis, 454 sequencing of the region upstream of IL-5, in collaboration with John Rioux and Jan Cools, have been unsuccessful to date. Whole genome sequencing of DNA from two family members has been completed and analysis is underway. We continue to follow affected family members for development of clinical manifestations. To date, there has been no progression of disease and markers of eosinophil activation have remained stable. In the past year, we have identified and/or characterized several novel subgroups of patients with eosinophilia. We studied four patients with episodic eosinophilia and angioedema and demonstrated that multiple lineages, including neutrophils, eosinophils and platelets, cycle with a 25-30 day periodicity. Eosinophil cycling is preceded by elevations in eosinophil related cytokines, including IL-5, GM-CSF and eotaxin, and followed by rises in inflammatory markers. Unlike cyclic neutropenia, mutations in ELANE do not appear to be involved. We have also identified 7 subjects with marked eosinophilia (>1,500/mm3) of >5 years duration and no evidence of clinical manifestations despite not being treated. Comparison of these subjects to patients with hypereosinophilic syndrome reveals that they are a heterogeneous group, but have little evidence of eosinophil activation. A multicenter study is being organized to examine and compare subjects who are asymptomatic despite marked eosinophilia to those who present without symptoms but go on to develop clinical disease. We have continued to study the effects of novel therapies for the treatment of hypereosinophilic syndromes, including monoclonal antibodies to IL-5 and the tyrosine kinase inhibitor, imatinib. Long-term (5 year) followup of subjects enrolled on a placebo-controlled study of the anti-IL-5 antibody, mepolizumab has just been 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. We have also begun to explore new therapeutic approaches for the treatment of refractory L-HES in collaboration with Dr. Dunleavy (NCI). Additionally, we have expanded our studies of monoclonal antibodies targeting IL-5 to explore the role of eosinophilia in post-treatment reactions in the filarial infection, loiasis, since we have previously demonstrated an association between eosinophilia and side effects of DEC treatment in these patients. A clinical study is currently underway to examine the effects of the anti-IL-5 antibody, reslizumab, on post-treatment side effects of DEC in patients with Loa loa infection.

通过使用超过 250 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，我们继续寻找区分嗜酸性粒细胞增多综合征变体的新标志物。对大量嗜酸性粒细胞增多症和/或肥大细胞增多症患者的血清和表面 IL-5 受体水平的评估表明，该受体的调节发生在体内。该受体的血清水平与嗜酸性粒细胞增多、IL-5和IL-13的血清水平以及嗜酸性粒细胞活化标志物相关。有趣的是，在没有嗜酸性粒细胞增多的系统性肥大细胞增多症患者中，血清受体水平也升高，并且与血清类胰蛋白酶和嗜酸性粒细胞活化的表面标志物相关。这些发现可能对最近开发的针对 IL-5 及其受体的治疗药物具有重要意义。我们之前描述过一个患有嗜酸性粒细胞增多综合征常染色体显性变异的家族，该变异映射到染色体 5q31-33。与 John Rioux 和 Jan Cools 合作，为鉴定导致这种情况的基因进行了详尽的尝试，包括候选基因测序、阵列 CGHY、表达分析、IL-5 上游区域的 454 测序，但迄今为止尚未成功。两名家庭成员 DNA 的全基因组测序已经完成，分析正在进行中。我们继续跟踪受影响的家庭成员的临床表现。迄今为止，疾病没有进展，嗜酸性粒细胞活化标志物保持稳定。在过去的一年中，我们已经识别和/或描述了嗜酸性粒细胞增多症患者的几个新亚组。我们研究了四名患有阵发性嗜酸性粒细胞增多症和血管性水肿的患者，并证明了多种谱系，包括中性粒细胞、嗜酸性粒细胞和血小板，以 25-30 天的周期循环。嗜酸性粒细胞循环之前，嗜酸性粒细胞相关细胞因子（包括 IL-5、GM-CSF 和嗜酸粒细胞趋化因子）升高，随后炎症标志物升高。与周期性中性粒细胞减少症不同，ELANE 突变似乎并不参与其中。我们还发现 7 名受试者有明显的嗜酸粒细胞增多症 (>1,500/mm3)，持续时间 >5 年，尽管未接受治疗，但没有临床表现的证据。这些受试者与嗜酸性粒细胞增多综合征患者的比较表明，他们是一个异质群体，但几乎没有嗜酸性粒细胞激活的证据。一项多中心研究正在组织中，以检查和比较尽管有明显嗜酸性粒细胞增多但无症状的受试者与没有症状但继续发展为临床疾病的受试者。我们继续研究治疗嗜酸性粒细胞增多综合征的新疗法的效果，包括 IL-5 的单克隆抗体和酪氨酸激酶抑制剂伊马替尼。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）随访刚刚完成。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。我们还开始与 Dunleavy 博士 (NCI) 合作，探索治疗难治性 L-HES 的新治疗方法。此外，我们还扩大了针对 IL-5 的单克隆抗体的研究，以探索嗜酸性粒细胞增多在丝虫感染、罗阿病治疗后反应中的作用，因为我们之前已经证明了这些患者的嗜酸性粒细胞增多与 DEC 治疗的副作用之间存在关联。。目前正在进行一项临床研究，以检查抗 IL-5 抗体 reslizumab 对 Loa loa 感染患者的 DEC 治疗后副作用的影响。