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: 8157109
• 负责人: Amy Klion
• 金额: $ 63.25万
• 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/8157109
• 关键词: Candidate Disease Gene; Disease; Drug Hypersensitivity; Eosinophilia; Pathogenesis; Tyrosine Kinase Inhibitor; eosinophil; human disease

Using a cohort of more than 200 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. This may have important implications in the setting of recently developed therapeutic agents targeting IL-5 and its receptor. We have developed an assay to examine the effects of such agents on IL-5 receptor bearing cells in the bone marrow using colony forming assays and flow cytometry. 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. High-throughput sequencing of the target region is planned. Fibrosis is one of the most severe complications of eosinophilia and is particularly prevalent in patients with untreated FIP1L1/PDGFRA-positive disease. We have recently completed microarray analysis using eosinophil RNA from FIP1L1/PDGFRA-positive patients before and after imatinib treatment in an effort to identify the factors responsible for the increased prevalence of fibrosis in this condition. Analysis is ongoing. 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. We have also begun to explore new therapeutic approaches for the treatment of refractory L-HES in collaboration with Drs. Janik and Morris (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.

通过使用 200 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。这可能对最近开发的针对 IL-5 及其受体的治疗药物的设置具有重要意义。我们开发了一种检测方法，使用集落形成检测和流式细胞术检查此类药物对骨髓中携带 IL-5 受体的细胞的影响。 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。 计划对目标区域进行高通量测序。 纤维化是嗜酸性粒细胞增多最严重的并发症之一，在未经治疗的 FIP1L1/PDGFRA 阳性疾病患者中尤其普遍。我们最近使用来自伊马替尼治疗前后 FIP1L1/PDGFRA 阳性患者的嗜酸性粒细胞 RNA 完成了微阵列分析，试图确定导致这种情况下纤维化患病率增加的因素。 分析正在进行中。 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。 我们还开始与 Drs. 合作探索治疗难治性 L-HES 的新治疗方法。贾尼克和莫里斯（NCI）。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。 。