Infections and The Stability of Transplantation Tolerance

感染和移植耐受的稳定性

• 批准号: 8512659
• 负责人: Anita S Chong
• 金额: $ 107.15万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-17 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512659
• 关键词: Acute; Address; Allografting; Animals; Apoptosis; Bacterial Infections; Biological Preservation; Cells; Clinic; Clinical; Clonal Deletion; Clonal Expansion; Data; Diagnosis; Diagnostic; Exhibits; Goals; Heart Transplantation; Human; Human Resources; Immune; Immune Tolerance; Immune response; Immunosuppression; Immunosuppressive Agents; Infection; Infectious Agent; Inflammatory; Instruction; Interferons; Interleukin-6; Investigation; Laboratories; Life; Listeria; Listeriosis; Long-Term Effects; Maintenance; Memory; Microsurgery; Monitor; Mus; Natural Immunity; Pattern recognition receptor; Pharmaceutical Preparations; Phase; Prevention; Progress Reports; Recurrence; Regimen; Regulation; Request for Applications; Research; Research Design; Research Infrastructure; Residual state; Resistance; Resources; Rodent Model; Signal Transduction; Stimulus; T cell anergy; T-Lymphocyte; TNFSF5 gene; Testing; Therapeutic; Time; Transplantation; Transplantation Immunology; Transplantation Tolerance; Virus Diseases; Work; adaptive immunity; anergy; animal breeding; arm; base; clinically relevant; cytokine; exhaustion; heart allograft; improved; insight; meetings; member; novel; pathogen; prevent; programs; response; success; transcription factor

PROJECT SUMMARY (See Instructions): Project Overview Transplantation tolerance Is a dynamic immunological state that accommodates graft acceptance whilst maintaining undiminished immune responses to pathogens. We have recently demonstrated that the induction and preservation of transplantation tolerance can be differentially Impacted by pathogens that elicit distinct innate and adaptive immune signatures. These and other recent observations from our laboratories have led us to hypothesize that the quality of the tolerant state, either at the time of induction or during the maintenance phase, and the type of infection determine the long-term fate of the allograft. This is a new application requesting support for a highly integrated program project focused on understanding the cellular mechanisms in T cells that are necessary for a robust and persistent state of transplantation tolerance (i.e., tolerance that resists reversal by infections and permits long-term preservation of allograft function) (Project 1; Alegre) and understanding the short-term and long-term effects of infections on an already established state of transplantation tolerance (Project 2; Chong). Two Cores support the work of the two projects in the program. The Administrative Core (Core A, Chong) will oversee the administration of the program including the coordination of Progress Reports and co-ordinate meetings with the Internal and External Advisory Boards. The Animal and Microsurgery Core (Core B, Alegre) will be responsible for animal breeding and heart transplantations necessary for the two scientific projects. The Alegre and Chong laboratories have already been functioning as an integrated, cooperative program. Our investigations are revealing the complexity of the tolerant state as well as an unexpectedly divergent impact of infections on tolerance. There are few existing paradigms to guide these studies, thus the formal infrastructure of a Program Project will allow us to more seamlessly share personnel, data, resources, and to generate new hypotheses. Interactions with the internal and external advisory board members will allow new hypotheses and research designs to be vigorously vetted and improved upon. Successful completion of this program project will result in novel mechanistic and diagnostic insights into how transplantation tolerance can persist inspite of recurrent infections and achieve long-term allograft survival superior to current therapies.

项目摘要（参见说明）：项目概述 移植耐受是一种动态的免疫状态，适应移植物的接受，同时保持对病原体的免疫反应不减弱。我们最近证明，引起不同先天性和适应性免疫特征的病原体可能会对移植耐受的诱导和维持产生不同的影响。这些以及我们实验室最近的其他观察结果 使我们假设耐受状态的质量（无论是在诱导时还是在维持阶段）以及感染的类型决定了同种异体移植物的长期命运。 这是一项新申请，要求支持高度集成的计划项目，重点是了解 T 细胞中的细胞机制，这些机制对于强健且持久的移植耐受状态（即抵抗感染逆转并允许长期保留同种异体移植物功能的耐受性）是必需的（项目 1；Alegre）并了解感染的短期和长期影响 已经建立的移植耐受状态（项目 2；Chong）。两个核心支持程序中两个项目的工作。行政核心（核心 A，Chong）将监督该计划的管理，包括协调进度报告并协调与内部和 外部顾问委员会。动物和显微外科核心（Core B，阿雷格里）将负责这两个科学项目所需的动物育种和心脏移植。 Alegre 和 Chong 实验室已经作为一个综合的合作项目发挥作用。我们的研究揭示了耐受状态的复杂性以及感染对耐受性的意外不同影响。指导这些研究的现有范式很少，因此计划项目的正式基础设施将使我们能够更无缝地共享人员、数据、资源，并产生新的假设。与内部和外部顾问委员会成员的互动将使新的假设和研究设计得到严格审查和改进。 该计划项目的成功完成将为移植耐受如何在反复感染的情况下持续存在并实现优于当前疗法的长期同种异体移植存活提供新的机制和诊断见解。