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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

基本信息

批准号：
9087093
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087093
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 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 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 adaptive immunity allograft rejection base career career development cell type effective therapy experience heart allograft heparanase immune activation improved outcome in vivo inhibitor/antagonist injured innovation isoimmunity knowledge base mouse model novel pathogen prevent receptor response sensor small molecule inhibitor targeted treatment therapy design

项目摘要

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）：本申请临床科学家发展奖（K08）提出了对先天免疫系统内源性激活剂在异位特异性T细胞激活中的作用的深入研究。候选人是一名免疫学家和移植外科医生，其长期目标是防止因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基础扩展到需要在这些新领域获得指导的新研究领域，从而实现发展奖的教育目标。导师的专业知识将对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表现至关重要。Thomas Coffman医学博士将提供炎症和移植小鼠模型方面的专业知识；Paul Noble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·奥尔森医学博士将在平衡外科和研究事业方面提供重要的指导。此外，候选人将参与本申请中概述的严格的职业发展计划，这将有助于确保候选人成功过渡到独立研究人员。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

DOI：
10.1016/j.clim.2018.03.002
发表时间：
2018-06
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
0
作者：
Weinhold KJ;Bukowski JF;Brennan TV;Noveck RJ;Staats JS;Lin L;Stempora L;Hammond C;Wouters A;Mojcik CF;Cheng J;Collinge M;Jesson MI;Hazra A;Biswas P;Lan S;Clark JD;Hodge JA
通讯作者：
Hodge JA

Dendritic Cell Therapy in Transplantation, Phenotype Governs Destination and Function.

移植中的树突状细胞治疗，表型决定目的地和功能。