Regulation, Memory and Inflammation in Transplantation

移植中的调节、记忆和炎症

• 批准号: 7644027
• 负责人: Laurence A Turka
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644027
• 关键词: Accounting; Adoptive Transfer; Affect; Alloantigen; Animal Model; Animals; Antigens; Area; CD4 Positive T Lymphocytes; Cells; Coupled; Data; Development; Effector Cell; Emigrant; Endothelial Cells; Engraftment; Equilibrium; Event; Generations; Goals; In Vitro; Infection; Inflammation; Knock-in Mouse; Knowledge; Laboratories; Lead; Light; MHC Class II Genes; Mediating; Memory; Modeling; Mus; Numbers; Other Resources; Outcome; Pathway interactions; Patients; Peripheral; Phase; Population; Predisposition; Primates; Process; Race; Regulation; Relative (related person); Reperfusion Injury; Reporter; Research Personnel; Residual state; Resistance; Rodent; Rodent Model; Role; Shapes; Signal Transduction; System; T memory cell; T-Cell Activation Pathway; T-Lymphocyte; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; Transplantation; Work; base; cell type; cytokine; design; in vivo; insight; programs; response; sensor; tool

Despite the "relative" ease of inducing transplant tolerance in some rodent models, the same approaches have often proven difficult to translate into larger animals and patients. One reason is that small animal models often fail to account for the barrier of memory. In addition to this known hurdle, increasing evidence indicates that inflammation (which may occur as a result of rejection, ischemia-reperfusion injury, infection etc.) can also inhibit tolerance induction. The central tenet of this project is that two events occurring very early during the process of engraftment, inflammation and antigen encounter, can determine graft outcome and tolerance susceptibility by modulating the balance between regulatory cells and effector/memory cells. Our theoretical framework is that engraftment initiates a "race" or "competition" between regulation and effector/memory development, and the result of this is crucial to the outcome of the graft. Our aims will test the hypotheses that: inflammation promotes the development of donor specific memory, while at the same time inhibiting the development of regulation (aim #1); that antigen encounter, in addition to its known effects on effector/memory development also shapes Treg development (aim #2), and that regulation which is "dysfunctional" in the context of memory, can nonetheless be harnessed to block memory responses if adjunctive approaches are use (aim #3). This work will be important for the studies in project #1, in particular those that focus on how the TIM1:TIM4 pathway effects Treg generation and conversion. .There will also be close interactions with project #3, particularly in the area of how cytokines and inflammation interact to affect memory and regulation, and how costimulatory blockade affects these processes. We bring a number of important tools that will be critical to.these studies. Through our ongoing interactions with Terry Strom and Mo Sayegh as part of the PPG, we have obtained foxp3-GFP knock-in mice. These valuable animals can be used to separately study the stability, expansion and function of naturally arising Tregs, and the conversion, expansion and function of antigen/cytokine-induced Tregs. In addition to these animals, other resources include MHC class II alloreactive TCR transgenic mice, MyD88- deficient mice, and crosses amongst all of these strains. Collectively, these studies will provide important new insights into the differentiation and fate of alloreactive T cells in vivo, define how these events are modulated by inflammation and antigen encounter, and explore approaches that will allow for the control of memory T cell responses by regulatory T cells.

尽管在某些啮齿动物模型中“相对”容易诱导移植耐受，但同样的方法 往往被证明很难转化为更大的动物和患者。其中一个原因是那只小动物 模型往往无法解释记忆的障碍。除了这个已知的障碍，越来越多的证据表明 提示炎症(可能是由于排斥反应、缺血再灌注损伤、感染 等)也可抑制耐受诱导。 这个项目的中心原则是，在植入过程中很早就发生了两件事， 炎症和抗原相遇可通过调节调节决定移植物的预后和耐受敏感性 调节细胞和效应/记忆细胞之间的平衡。我们的理论框架是 植入在调节和效应器/记忆发育之间引发了一场“竞赛”或“竞争”， 这一结果对移植物的结果至关重要。我们的目标将检验以下假设：炎症 促进供体特异性记忆的发展，同时抑制供体特异性记忆的发展 调节(目标1)；除了抗原对效应器/记忆发育已知影响外，还与其相遇 也塑造了Treg的发展(目标2)，以及在 如果使用附加方法(目标)，仍然可以利用内存来阻止内存响应 #3)。这项工作对于项目1中的研究将是重要的，特别是那些侧重于如何 TIM1：TIM4途径影响Treg的产生和转化。。还将与 项目3，特别是在细胞因子和炎症如何相互作用影响记忆和 监管，以及共刺激封锁如何影响这些过程。 我们带来了一些对这些研究至关重要的重要工具。通过我们正在进行的 与Terry Strom和Mo Sayegh的相互作用作为PPG的一部分，我们已经获得了Foxp3-GFP敲入 老鼠。这些珍贵的动物可以用来分别研究其稳定性、膨胀性和功能。 自然产生的Tregs，以及抗原/细胞因子诱导的Tregs的转换、扩增和功能。在……里面 除了这些动物，其他资源包括MHC II类同种异体反应TCR转基因小鼠，MyD88- 缺陷小鼠，并在所有这些品系中杂交。 总而言之，这些研究将为研究人与人之间的差异和命运提供重要的新见解 体内的同种异体反应性T细胞，定义这些事件是如何通过炎症和抗原相遇来调节的， 并探索允许调节性T细胞控制记忆T细胞反应的方法。