The Role of Innate Immune Cell Trafficking in Th2 Differentiation

先天免疫细胞运输在 Th2 分化中的作用

基本信息

批准号：
9923557
负责人：
Caroline Lauren Sokol
金额：
$ 20.09万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-23 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923557
关键词：
Advisory Committees Affect Allergens Allergic Allergic Disease Allergic inflammation Animals Antigen Presentation Antigen-Presenting Cells Antigens Area Award Basic Science Basophils Bioinformatics Blood CCL2 gene CCL7 gene CCL8 gene CCR8 gene Cell Differentiation process Cell Maturation Cells Chronic Disease Clinical Immunology Complement Cutaneous Data Dendritic Cells Dermal Development Disease Doctor of Medicine Doctor of Philosophy Emigrations Environment Foundations Funding General Hospitals Genomics Goals Grant Helper-Inducer T-Lymphocyte High Prevalence Hour Human Hypersensitivity IgE Immune Immune response Immunity Immunization Immunology In Vitro Inflammatory Innate Immune System Institution Interleukin-4 Laboratories Leadership Ligands Lipopolysaccharides Massachusetts Mediating Medicine Mentors Mentorship Mus Nature Outcome Papain Pathway interactions Peptide Hydrolases Peripheral Physicians Population Positioning Attribute Postdoctoral Fellow Process Production Publications Publishing Research Resources Role SELL gene Scientist Shapes Signal Transduction Skin Source System Systems Biology T cell response T-Lymphocyte Techniques Testing Tissues Training Training Activity Translational Research Universities Up-Regulation Work Writing base career catalyst cell motility cell type chemokine chemokine receptor cytokine draining lymph node effector T cell environmental allergen experimental study faculty research in vivo innate immune mechanisms instructor intravital microscopy medical schools microscopic imaging migration mouse allergen mouse model multidisciplinary novel therapeutics prevent receptor expression response responsible research conduct selective expression success trafficking transcriptome sequencing translational research program

项目摘要

PROJECT SUMMARY Candidate Caroline Sokol, M.D., Ph.D., is an Assistant in Medicine in the Allergy and Clinical Immunology Unit at Massachusetts General Hospital (MGH) and an Instructor of Medicine at Harvard Medical School (HMS). She received her M.D./Ph.D. from Yale University, where she studied the mechanisms of innate immune control of Th2 differentiation in the laboratory of Dr. Ruslan Medzhitov. Her work there led to two first author Nature Immunology publications on the role of basophils in initiating the allergic immune response and Th2 differentiation. It also led to her current work in the laboratory of Dr. Andrew Luster at the Center for Immunology and Inflammatory Diseases (CIID) at MGH, where she has focused on the role of innate immune cell trafficking in the activation and control of the allergic immune response and Th2 differentiation. The short- term goals of this K08 award application resubmission are to provide training in intravital microscopy, advanced genomic techniques, including RNA-Seq, human immunology and translational research. Dr. Sokol’s long-term goal is to develop an independent translational research program studying the innate immune control of allergic disease. The experiments, training activities, and mentoring plan outlined in this proposal will successfully position Dr. Sokol for her first R01 and an independent career as a physician-scientist. Mentorship, Training Activities, and Environment Dr. Sokol will perform the work outlined in this proposal in the CIID at MGH, under the mentorship of Dr. Andrew Luster. The CIID is a state-of-the-art multidisciplinary basic science research center focused on mechanisms of immune-mediated inflammatory diseases that serves as the foundation for immunology research at MGH. Dr. Luster is an expert in the fields of cellular trafficking and chemokine research, areas that are central to this application. Additionally, Dr. Luster has an excellent track record of mentorship, having mentored over 50 post-doctoral candidates, of which 17 are currently independently-funded research faculty at academic institutions. Additionally, Dr. Sokol has organized a Training Advisory Committee consisting of Drs. Nir Hacohen, Thorsten Mempel and Arlene Sharpe. They will provide expertise and hands-on training in advanced microscopic imaging, advanced genomic techniques, human immunology and translational research. To complement the expertise of her mentors, Dr. Sokol will complete didactic courses in bioinformatics and systems biology, grant writing, leadership, translational research, and the responsible conduct of research through the Harvard Catalyst. The collaborative opportunities, intellectual environment, and resources available to Dr. Sokol are outstanding and provide her with a clear path to independent success. Research Allergic diseases are characterized by inappropriate Type-2 immune responses targeted against non-infectious environmental allergens. Despite the high prevalence of allergic diseases, very little is known about how the innate immune system recognizes allergens and initiates the allergic immune response, which has limited research into novel therapeutics. Recent research has identified a specialized population of CD301b+ dendritic cells (DCs) located in murine skin that selectively migrates into the draining lymph node (dLN) and promotes Th2 differentiation in response to allergens. However, the pathways that promote this selective migration in response to allergens are unknown. We propose first, to define the chemokine pathways involved in the migration of CD301b+ DCs to the dLN. We show in preliminary data that allergen exposure results in the production of CCR8 ligands in the skin and dLN of mice, as well as in human skin explants. Furthermore, we provide preliminary data that in addition to CCR7 signals, CCR8 is necessary for the emigration of CD301b+ DCs from the skin and subsequent Th2 differentiation, while CCR2 prevents CD301b+ DC emigration to the dLN. However, control of CD301b+ DC migration is not the only mechanism for innate control of allergic immune initiation. Although CD301b+ DCs are necessary for Th2 differentiation, they are not sufficient to induce Th2 differentiation from naïve T cells. We next propose to determine the role and identity of accessory cells in promoting Th2 differentiation. We provide preliminary data that there is a required accessory cell that provides the necessary skewing information in tandem with antigen presentation and costimulation by DCs. These accessory cells enter the dLN via a CD62L-dependent process and the entry of this cell type corresponds with the entry of a previously undescribed IL-4 producing cell that we have identified. We believe that through the control of CD301b+ DC migration and the entry of this accessory cell, that the innate immune system precisely controls the outcome of T helper cell differentiation.

项目摘要候选人医学博士Caroline Sokol是过敏和临床免疫学部门的医学助理马萨诸塞州综合医院（MGH）和哈佛医学院（HMS）的医学讲师。她收到了她的M.D./ph.d。她从耶鲁大学研究了先天免疫控制机制 Ruslan Medzhitov博士实验室的Th2分化。她在那里的工作导致了两个第一作者大自然免疫学出版物关于嗜碱性粒细胞在发起过敏性免疫反应和TH2中作用的作用分化。这也导致了她目前在Andrew Luster博士实验室的工作 MGH的免疫学和炎症性疾病（CIID），她专注于先天免疫的作用细胞运输在激活和控制过敏性免疫反应和Th2分化中。短 - 该K08奖励申请重新提交的术语目标是提供插入显微镜的培训，先进的基因组技术，包括RNA-Seq，人类免疫学和转化研究。索科尔博士长期目标是制定研究先天免疫控制的独立翻译研究计划过敏性疾病。本提案中概述的实验，培训活动和心理计划将成功地将Sokol博士定位为她的第一个R01和独立的身体科学家职业。指导，培训活动和环境 Sokol博士将在MGH的CIID中概述的该提案中概述的工作，并在博士的指导下进行。安德鲁·兰斯（Andrew Luster）。 CIID是一个最新的多学科基础科学研究中心免疫介导的炎症性疾病的机制，作为免疫学的基础 MGH的研究。 Luster博士是细胞贩运和趋化因子研究领域的专家是此应用程序的核心。此外，Luster博士拥有Mentalship的出色记录，介绍了50多名博士后候选人，其中17名目前是由独立资助的研究学院学术机构。 Sokol博士的其他组织组织了一个由Drs组成的培训咨询委员会。 Nir Hacohen，Thorsten Mempel和Arlene Sharpe。他们将提供专业知识和动手培训先进的微观成像，晚期基因组技术，人类免疫学和转化研究。为了完成她的导师的专业知识，Sokol博士将完成生物信息学的教学课程系统生物学，赠款写作，领导力，翻译研究以及负责任的研究行为通过哈佛催化剂。协作机会，智力环境和资源 Sokol博士可用，非常出色，为她提供了独立成功的清晰途径。研究过敏性疾病的特征是针对非感染的不适当2型免疫调查环境过敏原。尽管过敏性疾病的患病率很高，但对先天免疫系统识别过敏原并启动过敏性免疫反应，该反应限制研究新疗法。最近的研究确定了CD301B+树突状的专业人群细胞（DC）位于鼠皮中，有选择地迁移到排水淋巴结（DLN）并促进响应过敏原的Th2分化。但是，促进这种选择性迁移的途径对过敏原的反应是未知的。我们首先建议定义涉及的趋化因子途径 CD301B+ DC迁移到DLN。我们在初步数据中显示，过敏原暴露导致小鼠皮肤和DLN以及人皮外植体中CCR8配体的产生。此外，我们提供初步数据，除了CCR7信号外，CCR8对于CD301B+的移民也是必需的来自皮肤的DC和随后的TH2分化，而CCR2则防止CD301B+ DC移民到 DLN。但是，控制CD301B+ DC迁移并不是唯一对过敏性控制的机制免疫主动性。尽管CD301B+ DC对于TH2分化是必需的，但它们不足诱导与幼稚T细胞的Th2分化。我们下一个建议确定的作用和身份辅助细胞促进Th2分化。我们提供必需的初步数据配件单元，提供与抗原呈现和 DCS的共刺激。这些附件单元通过CD62L依赖性过程进入DLN，并进入该单元格类型与我们已经鉴定出的先前未描述的IL-4产生细胞的输入相对应。我们认为，通过控制CD301B+ DC迁移和该附件单元的进入，先天免疫系统精确控制T辅助细胞分化的结果。