Vascular Endothelium Directs the Development of Regulatory T Cells

描述（由申请人提供）： 候选人的目标和职业发展计划：候选人是一名心胸外科医生，长期目标是成为一名学术医疗中心的独立调查员。该候选人已在基础免疫学研究中学习技能，特别关注移植免疫学。该奖项将提供必要的支持，以发展成功的长期调查所需的知识和技能的基础。这一基础将在该奖项的拟议五年内通过以下方式建立：（1）了解血管内皮细胞如何诱导同种异体调节性CD4+ T细胞，（2）了解先天免疫应答的激活如何影响这一过程，（3）获得关于免疫调节和先天免疫的详细知识，以及（4）收集数据，用于开发一个独立项目，以开发诱导对实体器官移植物免疫耐受的策略，特别关注肺移植。环境：圣路易斯华盛顿大学的环境在免疫学专业知识方面是丰富的。候选人的申办者是国内和国际公认的独立研究者，具有先天免疫和抗原呈递方面的专业知识。申请人的共同申办者是一位世界知名的肺移植外科医生，他也是公认的肺移植物缺血再灌注损伤的独立研究者。候选人有一个设备齐全的实验室和一个全职的研究技术员，其工资由该部支持。研究建议：这项资助计划的主要目的是研究血管内皮细胞和同种异体CD4+ T淋巴细胞之间相互作用的免疫学后果。初步数据表明，CD4+ T淋巴细胞与同种异体血管内皮细胞共培养后获得株特异性调节功能。我们计划确定这种诱导具有调节特性的CD4+ T淋巴细胞的机制。此外，我们将研究它们的产生和它们在体内模型中的调节特性，这些模型在我们的实验室中已经得到很好的描述。最后，初步数据表明，先天免疫系统的激活可能会破坏血管内皮细胞对具有调节特性的CD4* T细胞的诱导。我们计划研究先天免疫系统激活对这一过程的影响。(End摘要）

DESCRIPTION (provided by applicant): Candidate Goals and Career Development Plan: The candidate is a cardiothoracic surgeon with the long term goal of becoming an independent investigator in an academic medical center. The candidate has learned skills in basic immunological research with a special focus on transplantation immunology. This award will provide support needed to develop the foundation of knowledge and skills required for successful long-term investigation. This foundation will be built over the proposed five years of the award by (1) understanding how vascular endothelial cells induce allogeneic regulatory CD4+ T cells, (2) understanding how activation of innate immune responses influences this process, (3) acquiring detailed knowledge about immune regulation and innate immunity and (4) gathering data for the development of an independent project in developing strategies to induce immunological tolerance to solid organ grafts with a particular focus on lung transplantation. Environment: The environment at Washington University in St. Louis is rich in the availability of expertise in immunology in general. The candidate's sponsor is a nationally and internationally recognized independent investigator with expertise in innate immunity and antigen presentation. The applicant's co-sponsor is a world-renowned lung transplant surgeon, who is also well recognized as an independent investigator in ischemia-reperfusion injury of lung allografts. The candidate has a well-equipped laboratory and a full-time research technician whose salary is supported by the Department. Research Proposal: The primary aim of this grant proposal is to investigate the immunological consequences of interactions between vascular endothelium and allogeneic CD4+ T lymphocytes. Preliminary data indicate that CD4+ T lymphocytes acquire strain-specific regulatory function after co-culture with allogeneic vascular endothelial cells. We plan to identify the mechanism underlying this induction of CD4+ T lymphocytes with regulatory properties. Furthermore, we will examine their generation and their regulatory properties in vivo models that have been well described in our laboratory. Finally, preliminary data suggest that activation of the innate immune system may disrupt the induction of CD4* T cells with regulatory properties by vascular endothelial cells. We plan to study the impact of innate immune system activation on this process. (End of Abstract)