CC Chemokine-Mediated Differential Immunoregulation by Human Eosinophils

应聘者描述(由申请人提供)：候选人(Praveen Akuthota博士)是贝丝以色列女执事医学中心肺、重症监护和睡眠医学部以及过敏和炎症科的成员，也是哈佛医学院的医学系讲师。此次K08职业发展奖将培养他成为嗜酸性粒细胞免疫生物学独立研究员的职业目标。在获奖期间，职业发展计划将通过在彼得·韦勒博士的指导下开展拟议的研究并通过一系列教学经验来磨练他作为基本调查员的技能。贝丝以色列女执事医疗中心和哈佛医学院提供的环境非常适合该奖项的研究和职业发展部分的成功。该研究计划的重点是人类嗜酸性粒细胞的免疫生物学。长期以来，嗜酸性粒细胞一直被认为在哮喘和其他嗜酸性肺病中仅作为末端效应细胞发挥作用，通过释放细胞毒物质发挥作用。然而，越来越多的证据表明，嗜酸性粒细胞具有重要的多潜能免疫调节作用。嗜酸性粒细胞的不同免疫调节特性已经落后于其他免疫细胞类型。这种滞后可能是对包括哮喘在内的嗜酸性肺部疾病的病理生物学认识不完全的部分原因。候选人之前的工作已经确定CCR7的配体(CCL19和CCL21)是趋化因子，其对嗜酸性粒细胞的影响及其影响局部免疫环境的能力值得探索。拟议的研究将解决总体假设，即CCR7受体-配体在嗜酸性粒细胞上的相互作用在促进Th2炎症和组织嗜酸性粒细胞增多的过敏性呼吸道疾病中起着不可或缺的作用。为了解决这一总体假设，特定的目标将探讨以下机制：1)CCR19和CCL21刺激下的人嗜酸性粒细胞表达预分辨表型；2)暴露于CCR7配体的人嗜酸性粒细胞可防止淋巴细胞的Th2极化；3)CCR7缺乏的嗜酸性粒细胞过敏性呼吸道炎症增加。这些研究将利用从人类捐赠者的外周血液中分离出的人嗜酸性粒细胞和过敏性呼吸道炎症的小鼠模型。具体的实验设计包括细胞因子分泌的多重研究、嗜酸性粒细胞基因表达分析、嗜酸性粒细胞-淋巴细胞相互作用研究，以及利用嗜酸性粒细胞过继转移进行的小鼠研究。这项拟议的研究有可能为嗜酸性粒细胞对特定趋化因子刺激的不同反应提供见解，并有助于更好地理解嗜酸性粒细胞增多与肺部疾病的交集。

DESCRIPTION (provided by applicant): The Candidate (Dr. Praveen Akuthota) is a member of the Division of Pulmonary, Critical Care, and Sleep Medicine and of the Division of Allergy and Inflammation at Beth Israel Deaconess Medical Center and is an Instructor in Medicine at Harvard Medical School. This K08 Career Development Award will foster his career goal to become an independent investigator in eosinophil immunobiology. During the award period, the career development plan will allow for the honing of his skills as a basic investigator through carrying out the proposed research under the mentorship of Dr. Peter Weller and through a series of didactic experiences. The environment provided by Beth Israel Deaconess Medical Center and Harvard Medical School is ideally suited for the success of both the research and career development components of the award. The research plan focuses on the immunobiology of human eosinophils. Eosinophils have long been regarded to function exclusively as end-effector cells in asthma and other eosinophilic lung disorders, acting through the release of cytotoxic substances. However, mounting evidence has demonstrated that eosinophils have important multipotent immunoregulatory roles. Characterization of differential immunoregulation by eosinophils has lagged behind that of other immune cell types. This lag may be in part responsible for an incomplete understanding of the pathobiology eosinophilic pulmonary diseases, including asthma. The Candidate's previous work has identified the ligands of CCR7 (CCL19 and CCL21) as chemokines whose impacts on eosinophils and their capacity to influence the local immune environment warrant exploration. The proposed studies will address the overall hypothesis that CCR7 receptor-ligand interactions on eosinophils have an integral role in allergic airways disease that promotes resolution of Th2 inflammation and tissue eosinophilia. To address this overall hypothesis, Specific Aims will investigate the mechanism by which: 1) Human Eosinophils Express a Pro-Resolution Phenotype with CCL19 and CCL21 Stimulation; 2) Human Eosinophils Exposed to CCR7 Ligands Prevent Th2 Polarization of Lymphocytes; 3) Allergic Airway Inflammation Is Increased in Mice with CCR7-Deficient Eosinophils. These studies will utilize human eosinophils isolated from the peripheral blood of human donors and murine models of allergic airways inflammation. Specific experimental designs include multiplex-based studies of cytokine secretion, eosinophil gene expression analysis, eosinophil-lymphocyte interaction studies, and murine studies utilizing eosinophil adoptive transfer. The proposed research has the potential to provide insights into differential eosinophil responses to specific chemokine stimuli and lead to improved understanding of the intersection of eosinophilia and pulmonary disease.