Improved survival in sepsis with LFA-1blockade evaluation of lymphocyte activatio

LFA-1 阻断评估淋巴细胞活化可提高脓毒症患者的生存率

基本信息

批准号：
8679938
负责人：
Kevin Wayne McConnell
金额：
$ 19.44万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-03 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8679938
关键词：
Activated Lymphocyte Adhesions Adoptive Transfer Affect Animal Model Annexins Antibodies Antigen-Presenting Cells Antigens Apoptosis Binding Biological Assay Cell Communication Cell Death Cells Cessation of life Clinical Trials Collaborations Communication Competence Critical Illness Data Development Plans Disease Disease Outcome Endothelium Evaluation Event Experimental Designs Flow Cytometry Fostering Functional disorder Funding Goals Grant Immune Immune response Immunohistochemistry Immunology Immunophenotyping Infiltration Inflammation Inflammatory Response Injury Integrins Intercellular adhesion molecule 1 Interferons K-Series Research Career Programs Laboratories Lead Leukocyte Adhesion Molecules Leukocyte-Adhesion Receptors Leukocytes Ligands Ligation Lymphocyte Lymphocyte Activation Lymphocyte Depletion Lymphocyte Function Lymphocyte Subset Manuscripts Mediating Mentors Mentorship Modeling Monoclonal Antibodies Mus Organ Organ Transplantation Paralysed Patients Pattern Phase Physiological Play Population Population Decreases Predisposition Process Proliferation Marker Puncture procedure Recording of previous events Research Research Personnel Role Scientist Sepsis Signal Transduction Site Solid Staining method Stains Surgeon T-Lymphocyte TNF gene Therapeutic Time Tissues Training Programs Translational Research Translations United States United States National Institutes of Health Work Writing apoptosis in lymphocytes career development cell killing congenic cytokine cytotoxic efalizumab exhaustion immunological synapse improved in vivo insight intercellular cell adhesion molecule knowledge base migration prevent programs public health relevance research study response restoration secondary infection septic skills therapeutic target trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): The goal of this mentored clinician scientist career development award is to establish a productive translational research program in sepsis immunology that will foster my transition to an independent surgeon- scientist. This training program utilizes a mentored research plan with guidance from Drs. Coopersmith, Kirk, and Ford - experts in sepsis and immunology and established NIH funded researchers, who have a history successful mentorship. My 5 year career development plan gradually builds toward independence. My mentors and I have selected opportunities to broaden my knowledge base, expand technical and experimental design skills, enhance scientific collaboration and communication, develop my laboratory management skills, and mature my grant and manuscript writing. Because more than 210,000 patients die from sepsis per year in the United States, a better understanding of its progression and pathophysiology is critical. Alterations in lymphocyte function and apoptosis have been shown to play an important role in both animal models of sepsis and in septic patients. The scientific approach in this proposal evaluates essential components of the lymphocyte immune response, activation and trafficking, which are poorly understood in sepsis. We propose a multiple compartment and multiple time point analysis of lymphocyte subsets to evaluate the progression of activation and how trafficking is altered in sepsis. In addition, we use a monoclonal antibody to leukocyte function antigen-1 (LFA-1), essential to both lymphocyte activation and trafficking, to evaluate how this process can be modulated for therapeutic benefit. LFA-1 interaction with ICAM-1 promotes lymphocyte activation and co-stimulatory signal transmission and is also involved in firm adhesion and migration of lymphocytes across the endothelium. We hypothesize that LFA- 1 blockade could be beneficial in the early and late phases of sepsis by limiting activation of lymphocytes, decreasing cytokine secretion, and limiting progression to lymphocyte exhaustion. In addition data from ICAM-/- mice shows decreased organ damage in murine sepsis. Thus, blocking LFA-1-mediated trafficking of lymphocytes to inflamed tissue could limit local tissue damage and propagation of the inflammatory response in sepsis. In our preliminary studies, blockade of LFA-1, after induction of sepsis, leads to a significant improvement in survival in a lymphocyte dependent manner. This proposal will identify how lymphocyte activation and trafficking progress in sepsis and how LFA-1 blockade mediates its beneficial effect. In addition, we will use adoptive transfer of activated cells to evaluate how activation contributes to trafficking in sepsis. Finally, we evaluate how these processes alter the immune paralysis and secondary infections seen in the late phase of sepsis. This work will provide both the necessary scientific data and mentorship needed for my transition to an independent scientist and may lead to translation of these findings to critically ill patients.

描述（由申请人提供）：这个受过指导的临床医生职业发展奖的目标是建立败血症免疫学的生产转化研究计划，该计划将促进我向独立外科医生的过渡。该培训计划利用DRS的指导利用了指导的研究计划。库珀史密斯，柯克和福特 - 败血症和免疫学专家，并建立了NIH资助的研究人员，他们拥有成功的指导。我的5年职业发展计划逐渐建立在独立方面。我和我的导师选择了机会来扩大我的知识基础，扩大技术和实验设计技能，增强科学合作和沟通，发展我的实验室管理技能，并成熟我的赠款和手稿写作。由于在美国，每年有21万名患者死于败血症，因此对其进展和病理生理学的更好理解至关重要。淋巴细胞功能和凋亡的改变已显示出在败血症和化脓性患者的动物模型中起重要作用。该提案中的科学方法评估了淋巴细胞免疫反应，激活和贩运的基本组成部分，这些组成部分在败血症中尚未理解。我们提出了淋巴细胞亚群的多个隔室和多个时间点分析，以评估激活的进展以及败血症中的运输方式改变。此外，我们使用对白细胞功能抗原-1（LFA-1）的单克隆抗体，对淋巴细胞激活和运输至关重要，以评估如何调节此过程以进行治疗益处。 LFA-1与ICAM-1的相互作用促进淋巴细胞的激活和共刺激性信号传递，并且还参与了整个内皮细胞淋巴细胞的牢固粘附和迁移。我们假设通过限制淋巴细胞的激活，减少细胞因子的分泌并将进展限制为淋巴细胞的衰竭，LFA-1封锁在败血症的早期和晚期可能是有益的。此外，来自ICAM - / - 小鼠的数据显示，鼠败血症的器官损伤减少了。因此，阻止LFA-1介导的淋巴细胞对炎症组织的运输可能会限制脓毒症中炎症反应的局部组织损伤和传播。在我们的初步研究中，LFA-1诱导败血症后的阻滞导致淋巴细胞依赖性方式的存活率显着提高。该提案将确定败血症中淋巴细胞的激活和运输进展如何以及LFA-1封锁如何介导其有益作用。此外，我们将利用活化细胞的产物转移来评估激活如何有助于败血症的运输。最后，我们评估了这些过程如何改变败血症晚期的免疫麻痹和继发感染。这项工作将提供我向独立科学家的过渡所需的必要科学数据和指导，并可能导致这些发现转化为重病患者。