Eosinophil Recruitment and Activation in Solid Tumors

实体瘤中嗜酸性粒细胞的募集和激活

• 批准号: 7540370
• 负责人: JAMES Joseph LEE
• 金额: $ 29.4万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-10 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540370
• 关键词: Ablation; Affect; Allergens; Allergic; Antibodies; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Lineage; Cells; Clinical; Clinical Research; Colon; Cytoplasmic Granules; Data; Detection; Diphtheria Toxin; Electron Microscopy; Eosinophil Granule Proteins; Eosinophilia; Foundations; Genes; Goals; Growth; Immune response; Infiltration; Injection of therapeutic agent; Interleukin-5; Kinetics; Knock-out; Knockout Mice; Leukocytes; Lung diseases; Mammary gland; Melanoma Cell; Modeling; Mus; Neoplasm Metastasis; Pancreas; Phenotype; Proteins; Reagent; Recruitment Activity; Role; Solid Neoplasm; Structure; T-Lymphocyte; Testing; Time; Tissues; Transgenic Animals; Transgenic Mice; eosinophil; eosinophil peroxidase; experience; malignant breast neoplasm; mouse model; novel; response; suicide gene; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The infiltration and accumulation of eosinophils in solid tumors has been recognized as a correlative clinical feature of several tumor types, including colon, pancreatic, and breast cancers. This eosinophil recruitment also occurs in many mouse models of tumorigenesis. Despite the abundance of clinical studies and the availability of mouse models, eosinophil effector functions in general are poorly understood and, indeed, questions remain as to the role(s), if any, of these leukocytes. Studies of tumor associated eosinophils in the mouse have remained equivocal, in part, due to the lack of specific reagents and models with which to define unequivocally mechanisms of effector function. The goal of this proposal is to bridge this gap by exploiting our extensive experience examining eosinophil activities using allergen provocation models of lung disease. For example, we have created several specific antibodies that allow unambiguous detection of infiltrating eosinophils and the release of granule proteins (i.e., activation leading to degranulation). In addition, we have developed several knockout mice deficient of the predominant granule proteins that will permit assessments of degranulation. We have also developed a novel line of transgenic mice congenitally devoid of eosinophils. The ablation of eosinophils in these transgenic animals was accomplished through the expression of a suicide gene (i.e., Diphtheria Toxin A) exclusively in eosinophil-lineage cells and provides a unique opportunity to define eosinophil responses to tumors. This proposal utilizes these novel models and reagents to test the hypothesis that eosinophils modulate tumor onset/growth. Our objectives will be achieved by completing the following Specific Aims: (1) To define the kinetics of eosinophil recruitment to solid tumors as well as the extent of eosinophil activation/degranulation within tumors to which they have been attracted; (2) To determine the extent to which eosinophil-associated host responses modulate mammary gland tumor onset, growth kinetics, or rate of metastasis; (3) To determine whether eosinophil degranulation (i.e., the release of toxic cationic secondary granule proteins) has direct effects on mammary gland tumors.

描述（由申请人提供）：实体瘤中嗜酸性粒细胞的浸润和积聚已被认为是多种肿瘤类型的相关临床特征，包括结肠癌、胰腺癌和乳腺癌。这种嗜酸性粒细胞募集也发生在许多肿瘤发生的小鼠模型中。尽管有大量的临床研究和小鼠模型的可用性，但人们对嗜酸性粒细胞效应器功能的了解仍然很少，事实上，对于这些白细胞的作用（如果有的话）仍然存在疑问。对小鼠肿瘤相关嗜酸性粒细胞的研究仍然模棱两可，部分原因是缺乏明确定义效应功能机制的特定试剂和模型。该提案的目标是通过利用我们使用肺部疾病的过敏原激发模型检查嗜酸性粒细胞活动的丰富经验来弥补这一差距。例如，我们创建了几种特异性抗体，可以明确检测浸润的嗜酸性粒细胞和颗粒蛋白的释放（即激活导致脱颗粒）。此外，我们还开发了几种缺乏主要颗粒蛋白的敲除小鼠，可以对脱颗粒进行评估。我们还开发了一种新的转基因小鼠品系，其先天性地缺乏嗜酸性粒细胞。这些转基因动物中嗜酸性粒细胞的消融是通过仅在嗜酸性粒细胞谱系细胞中表达自杀基因（即白喉毒素A）来完成的，并为定义嗜酸性粒细胞对肿瘤的反应提供了独特的机会。该提案利用这些新颖的模型和试剂来检验嗜酸性粒细胞调节肿瘤发生/生长的假设。我们的目标将通过完成以下具体目标来实现：（1）确定实体瘤中嗜酸性粒细胞募集的动力学以及肿瘤内嗜酸性粒细胞被吸引的活化/脱颗粒的程度； (2) 确定嗜酸性粒细胞相关宿主反应调节乳腺肿瘤发病、生长动力学或转移率的程度； (3) 确定嗜酸性粒细胞脱颗粒（即有毒阳离子次级颗粒蛋白的释放）是否对乳腺肿瘤有直接影响。