Role of Endogenous Toll-Like Receptor Ligands in Allospecific T Cell Activation

内源性 Toll 样受体配体在同种异体 T 细胞激活中的作用

• 批准号: 8495927
• 负责人: Todd Victor Brennan
• 金额: $ 12.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495927
• 关键词: Address; Affect; Agonist; Allogenic; Allografting; Antigen-Presenting Cells; Applications Grants; Area; Award; Bacterial Infections; Binding; Biological Assay; Biological Response Modifiers; Brain Death; Cells; Critical Pathways; Data; Dendritic Cells; Detection; Development; Development Plans; Doctor of Philosophy; Ensure; Environment; Equilibrium; Extracellular Matrix; Figs - dietary; Genes; Glycobiology; Goals; Graft Rejection; Heart Transplantation; Heparitin Sulfate; Immune; Immune response; Immune system; Immunologist; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Injury; Inorganic Sulfates; Interferons; Investigation; Ischemia; K-Series Research Career Programs; Kinetics; Knockout Mice; Lead; Length; Leukocytes; Ligands; Measures; Mediating; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Mission; Modeling; Molecular; Mus; Mycoses; Myelogenous; Natural Immunity; Operative Surgical Procedures; Organ; Organ Donor; Organ Transplantation; Outcome; Pathway interactions; Pattern; Performance; Phosphorylation; Phosphotransferases; Polysaccharides; Process; Protease Inhibitor; Protein C Inhibitor; Receptor Activation; Regulation; Reperfusion Injury; Research; Research Personnel; Risk; Role; Route; Serum; Signal Transduction Pathway; Source; Sterility; T cell response; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TLR4 gene; Therapeutic; Time; Tissues; Toll-like receptors; Transgenic Mice; Transplant Recipients; Transplant Surgeon; Transplantation; Trauma; United States; Unspecified or Sulfate Ion Sulfates; Virus Diseases; Work; allograft rejection; base; career; career development; cell type; experience; heart allograft; heparanase; immune activation; improved; in vivo; inhibitor/antagonist; injured; innovation; isoimmunity; knowledge base; mouse model; novel; pathogen; prevent; receptor; response; sensor; small molecule; therapy design

DESCRIPTION (provided by applicant): This application for a Mentored Clinical Scientist Development Award (K08) proposes a thorough investigation into the role of endogenous activators of the innate immune system in allospecific T cell activation. The candidate is an immunologist and transplant surgeon whose long-term goal is to prevent loss of transplanted organs due to immune rejection. This proposal will fulfill the educational objective of the development award by facilitating the expansion of the applicant's knowledge base into novel lines of inquiry requiring mentorship in these new areas. The expertise of the mentors assisting in this grant proposal will be essential to the successful completion of both the educational mission of the award as well as the performance of the proposed research plan that spans these areas. Thomas Coffman, MD will provide expertise in inflammation and mouse models of transplantation; Paul Noble, MD will provide expertise in glycobiology and has extensive experience investigating endogenous innate immune agonists; John Olson, MD, PhD will provide critical mentorship on balancing careers in surgery and research. Additionally, the candidate will participate in a rigorous career development plan as outlined in this application that will be instrumental in ensuring the successful transition of this candidate to being an independent researcher. PROJECT SUMMARY: With the discovery of Toll-like receptors (TLRs) there has been an increased appreciation of the critical role of innate immune pathways in regulating adaptive immune responses. It is now recognized that endogenous molecules derived from tissue injury can serve as TLR ligands. In the setting of transplantation, donor organs are subjected to many potential sources of sterile tissue injury, including: donor brain death, prolonged ischemia time, reperfusion injury, surgical trauma, and immunological injury. Importantly, each of these factors is associated with increased risk of graft rejection. How graft injury specifically contributes to graft rejection, however, is unknown. Based on preliminary data, this work hypothesizes that heparan sulfate (HS), an extracellular matrix polysaccharide released during injury, acts as a damage-associated molecular pattern (DAMP) molecule that activates TLR4 and can promote allospecific T cell activation. The proposed work will: 1) define the molecular pathways by which HS activates allospecific T cells, 2) determine how modulation of HS serum levels in a murine cardiac transplantation model affects the kinetics of graft rejection, and 3) define the role of hot and graft innate immune responses in allospecific T cell activation. This proposed work is innovative, in that it systematically investigates a new pathway of immune stimulation in the setting of sterile tissue injury that has implications for how organ grafts are preserved for transplantation, the detection of graft rejection, and the potential treatment of graft rejection. he approach uses novel transgenic mouse models to investigate donor and recipient contributions to innate immune stimulation and the activation of T cell subsets with direct and indirect allospecificity. PROJECT RELEVANCE: The proposed work is directly relevant to understanding fundamental mechanisms of immune activation by tissue injury and to developing therapeutic approaches for mitigating these responses in order to improve outcomes in organ transplantation.

描述（由申请人提供）：本指导临床科学家发展奖 (K08) 申请建议对先天免疫系统内源性激活剂在同种异体特异性 T 细胞激活中的作用进行彻底研究。候选人是一名免疫学家和移植外科医生，其长期目标是防止由于免疫排斥而导致移植器官的损失。该提案将通过促进申请人的知识库扩展到需要这些新领域指导的新颖探究领域来实现发展奖的教育目标。协助这项资助提案的导师的专业知识对于成功完成该奖项的教育使命以及跨越这些领域的拟议研究计划的执行至关重要。 Thomas Coffman 医学博士将提供炎症和小鼠移植模型方面的专业知识； Paul Noble 医学博士将提供糖生物学方面的专业知识，并在研究内源性先天免疫激动剂方面拥有丰富的经验；约翰·奥尔森 (John Olson) 医学博士、博士将为平衡手术和研究职业提供重要指导。此外，候选人将参与本申请中概述的严格职业发展计划，这将有助于确保该候选人成功过渡为独立研究员。 项目摘要：随着 Toll 样受体 (TLR) 的发现，人们越来越认识到先天免疫途径在调节适应性免疫反应中的关键作用。现在人们认识到源自组织损伤的内源性分子可以充当 TLR 配体。在移植过程中，供体器官会遭受许多潜在的无菌组织损伤，包括：供体脑死亡、缺血时间延长、再灌注损伤、手术创伤和免疫损伤。重要的是，这些因素中的每一个都与移植排斥风险增加相关。然而，移植物损伤如何具体导致移植物排斥尚不清楚。基于初步数据，这项工作假设硫酸乙酰肝素 (HS)（一种损伤过程中释放的细胞外基质多糖）充当损伤相关分子模式 (DAMP) 分子，激活 TLR4 并促进同种异体特异性 T 细胞激活。拟议的工作将：1) 定义 HS 激活同种异体 T 细胞的分子途径，2) 确定小鼠心脏移植模型中 HS 血清水平的调节如何影响移植物排斥的动力学，3) 定义热和移植先天免疫反应在同种异体 T 细胞激活中的作用。这项拟议的工作具有创新性，因为它系统地研究了无菌组织损伤情况下免疫刺激的新途径，这对器官移植物如何保存用于移植、移植物排斥的检测以及移植物排斥的潜在治疗具有影响。该方法使用新型转基因小鼠模型来研究供体和受体对先天免疫刺激以及具有直接和间接同种异体特异性的 T 细胞亚群激活的贡献。 项目相关性：拟议的工作与了解组织损伤免疫激活的基本机制以及开发减轻这些反应的治疗方法以改善器官移植的结果直接相关。