Infections and The Stability of Transplantation Tolerance

项目概要（见说明）：项目概述 移植耐受是一种动态的免疫学状态，其适应移植物接受，同时维持对病原体的免疫应答不减弱。我们最近证明，诱导和保存移植耐受性可以受到病原体的不同影响，这些病原体引起不同的先天性和适应性免疫特征。这些以及我们实验室最近的其他观测结果 已经使我们假设，无论是在诱导期还是在维持期，耐受状态的质量以及感染的类型决定了同种异体移植物的长期命运。 这是一个新的申请，要求支持一个高度集成的程序项目，重点是了解T细胞中的细胞机制，这是一个强大的和持久的移植耐受状态所必需的（即，抵抗感染逆转并允许长期保存同种异体移植物功能的耐受性）（项目1;阿莱格雷），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）。两个核心支持该计划中两个项目的工作。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 外部咨询委员会。动物和显微外科核心（核心B，阿莱格雷）将负责两个科学项目所需的动物育种和心脏移植。 阿莱格雷和冲实验室已经作为一个综合的合作项目运作。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想不到的不同影响。现有的范例很少，以指导这些研究，因此，一个程序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。与内部和外部咨询委员会成员的互动将使新的假设和研究设计得到大力审查和改进。 该项目的成功完成将导致新的机制和诊断的见解移植耐受如何持续尽管复发性感染，并实现长期移植物存活上级目前的治疗。

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.