Laboratory Assessment of Patients with Hypereosinophilic Syndrome

嗜酸性粒细胞增多综合征患者的实验室评估

• 批准号: 8952883
• 负责人: Irina Maric
• 金额: --
• 依托单位: CLINICAL CENTER
• 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/8952883
• 关键词: Allergic; Antibodies; Biological Assay; Biopsy Specimen; Blood; Bone Marrow; Bone Marrow Cells; CD34 gene; Cell Line; Cells; Chronic eosinophilic leukemia; Clinical Trials; Diagnosis; Disease; Disseminated eosinophilic collagen disease; Eosinophilia; Epidermal Growth Factor Receptor; Flow Cytometry; Helminths; Hormone Receptor; Human; Hypersensitivity; IgG1; Imatinib mesylate; In Vitro; Infection; Laboratories; Laboratory Study; Lymphocyte; Macaca fascicularis; Mediating; Monkeys; Mucins; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Neoplasms; PDGFRA gene; Patients; Peripheral Blood Eosinophilia; Plasma; Population; Protein Tyrosine Kinase; Reaction; Serum; Shapes; Specimen; Subgroup; Surface; T-Lymphocyte; Tissues; Tryptase; Variant; cytokine; eosinophil; fusion gene; in vivo; killings; mRNA Expression; mast cell; novel; response; therapeutic target

Although several novel agents are currently in clinical trials for eosinophilic disorders, none has demonstrated efficacy in reducing blood and tissue eosinophilia in all subjects. Additional treatment approaches are clearly needed. We sought to explore the potential of the human eosinophil surface receptor epidermal growth factor-like module containing mucin-like hormone receptor 1 (EMR1) as a therapeutic target for eosinophilic disorders. EMR1 expression was assessed in blood and bone marrow specimens from eosinophilic and healthy subjects, cell lines, CD34(+) cells differentiated in vitro, and tissue biopsy specimens by using flow cytometry, quantitative PCR, and immunostaining. Eosinophil targeting by a novel, humanized, afucosylated anti-EMR1 IgG1 was evaluated in vitro by using a natural killer cell-mediated killing assay and in vivo in cynomolgus monkeys. Analysis of blood and bone marrow cells from healthy and eosinophilic donors and in vitro-differentiated CD34(+) cells confirmed restriction of human EMR1 surface and mRNA expression to mature eosinophils. Tissue eosinophils also expressed EMR1. Although EMR1 was highly expressed on eosinophils from all subjects, surface expression was negatively correlated with absolute eosinophil counts (r = -0.46, P < .001), and soluble plasma levels correlated positively with absolute eosinophil counts (r = 0.69, P < .001), suggesting modulation of EMR1 in vivo. Nevertheless, afucosylated anti-EMR1 mAb dramatically enhanced natural killer cell-mediated killing of eosinophils from healthy and eosinophilic donors and induced a rapid and sustained depletion of eosinophils in monkeys. These studies showed that EMR1 expression is restricted to mature blood and tissue eosinophils. Targeting of eosinophils with afucosylated anti-EMR1 antibody shows promise as a novel treatment for eosinophilic disorders.

尽管目前有几种新型药物正在进行嗜酸性粒细胞性疾病的临床试验，但没有一种药物在所有受试者中均显示出降低血液和组织嗜酸性粒细胞增多的疗效。显然需要采取其他治疗方法。 我们试图探索人嗜酸性粒细胞表面受体表皮生长因子样模块含有粘蛋白样激素受体1（EMR 1）作为嗜酸性粒细胞疾病的治疗靶点的潜力。 通过流式细胞术、定量PCR和免疫染色，评估了嗜酸性粒细胞和健康受试者的血液和骨髓标本、细胞系、体外分化的CD 34（+）细胞以及组织活检标本中的EMR 1表达。通过使用自然杀伤细胞介导的杀伤试验在体外和食蟹猴体内评价了新型人源化无岩藻糖基化抗EMR 1 IgG 1的嗜酸性粒细胞靶向作用。 对来自健康和嗜酸性粒细胞供体的血液和骨髓细胞以及体外分化的CD 34（+）细胞的分析证实了人EMR 1表面和mRNA表达对成熟嗜酸性粒细胞的限制。组织嗜酸性粒细胞也表达EMR 1。尽管EMR 1在所有受试者的嗜酸性粒细胞上高度表达，但表面表达与绝对嗜酸性粒细胞计数呈负相关（r =-0.46，P <0.001），可溶性血浆水平与绝对嗜酸性粒细胞计数呈正相关（r = 0.69，P <0.001），表明体内EMR 1的调节。然而，无岩藻糖基化抗EMR 1 mAb显著增强了自然杀伤细胞介导的对健康和嗜酸性粒细胞供体嗜酸性粒细胞的杀伤，并诱导猴中嗜酸性粒细胞的快速和持续耗竭。 这些研究表明，EMR 1的表达仅限于成熟的血液和组织嗜酸性粒细胞。用无岩藻糖基化抗EMR 1抗体靶向嗜酸性粒细胞显示出作为嗜酸性粒细胞疾病的新治疗的前景。