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: 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
• 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

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.

使用一组有250多名患有多种嗜酸性疾病的受试者，从良性嗜酸性粒细胞到嗜酸性粒细胞性白血病，我们一直在寻找区分过度粒细胞综合征的变体的新标记。 在大量嗜酸性粒细胞和/或肥大细胞增多症患者中，评估血清和表面IL-5受体水平，这表明该受体的调节发生在体内。受体的血清水平与嗜酸性粒细胞，IL-5和IL-13的血清水平以及嗜酸性粒细胞活化的标志物相关。有趣的是，无嗜酸性粒细胞增多症的全身性肥大性患者的血清受体水平也升高，并且与嗜酸性粒细胞激活的血清胰蛋白酶和表面标记相关。 这些发现可能在靶向IL-5及其受体的最近开发的治疗剂的环境中具有重要意义。 我们先前已经描述了一个具有异渗粒细胞综合征常染色体显性型变体的家族，该综合征将其映射到5q31-33染色体。详尽的尝试识别负责这种情况的基因，包括候选基因测序，阵列CGHY，表达分析，454与John Rioux和Jan Rioux和Jan Cools合作对IL-5上游的区域进行了454测序，这是没有成功的。 来自两个家庭成员的DNA的整个基因组测序已经完成，并且正在进行分析。我们继续跟随受影响的家庭成员开发临床表现。迄今为止，还没有疾病的进展，嗜酸性粒细胞激活的标志物保持稳定。 在过去的一年中，我们已经确定和/或表征了嗜酸性粒细胞菌患者的几个新型亚组。 我们研究了四名嗜酸性嗜酸性粒细胞和血管性水肿的患者，并证明了包括中性粒细胞，嗜酸性粒细胞和血小板在内的多个谱系，具有25-30天的周期性。嗜酸性粒细胞循环之前是嗜酸性粒细胞相关的细胞因子（包括IL-5，GM-CSF和Eotaxin）的升高，然后在炎症标记中升高。与环状中性粒细胞减少症不同，Elane突变似乎不涉及。 我们还确定了7名嗜酸性粒细胞菌（> 1,500/mm3）> 5年的受试者，尽管未接受治疗，但没有临床表现的证据。这些受试者与过度粒细胞综合征患者的比较表明，它们是异质组，但几乎没有嗜酸性粒细胞激活的证据。正在组织一项多中心研究，以检查和比较，尽管嗜酸性粒细胞增多显着，但与没有症状但继续发展临床疾病的人。 我们继续研究新疗法对治疗嗜酸性疾病综合征的影响，包括对IL-5的单克隆抗体和酪氨酸激酶抑制剂伊马替尼。 对抗IL-5抗体的安慰剂对照研究的长期随访（5年）随访，Mepolizumab刚刚完成。该药物在大多数受试者中继续表现出极好的功效，并且与毒性或中和抗体的发展无关。我们还开始探索与Dunleavy博士（NCI）合作治疗难治性L-HE的新治疗方法。此外，我们已经扩展了针对IL-5的单克隆抗体的研究，以探索嗜酸性粒细胞性嗜酸性粒细胞在治疗后反应中的作用，因为我们先前已经证明了这些患者的嗜酸性粒细胞和DEC治疗的副作用之间的关联，因为我们以前证明了这些患者的副作用。目前正在进行一项临床研究，以检查抗IL-5抗体Reslizumab对DEC在LOA LOA感染患者中的治疗后副作用的影响。