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诱导移植耐受性的“相对易于​​”，但相同的方法 经常被证明很难转化为较大的动物和患者。原因之一是那只小动物 模型通常无法解释内存的障碍。除了这个已知的障碍，越来越多的证据 表明炎症（可能是由于排斥反应，缺血 - 灌注损伤，感染而发生的 等）也可以抑制耐受性诱导。 该项目的核心宗旨是，在植入过程中很早就发生了两个事件， 炎症和抗原相遇，可以通过调节来确定移植物的结果和耐受性敏感性 调节细胞与效应子/记忆细胞之间的平衡。我们的理论框架是 植入在监管和效应子/记忆发展之间启动“种族”或“竞争”， 结果对移植的结果至关重要。我们的目标将检验以下假设：发炎 促进捐赠者特定记忆的发展，同时抑制 法规（AIM＃1）;除了已知对效应子/记忆发展的已知影响外，这种抗原相遇 还塑造了Treg开发（AIM＃2），以及在 记忆，如果使用辅助方法 ＃3）。这项工作对于项目1的研究将很重要，特别是那些关注如何关注的研究 TIM1：TIM4途径影响Treg的产生和转换。 。也将与 项目3，特别是在细胞因子和炎症如何相互作用以影响记忆和 调节以及con杀的封锁如何影响这些过程。 我们带来了许多重要的工具，这些工具对这些研究至关重要。通过我们的持续 作为PPG的一部分，与Terry Strom和Mo Sayegh的相互作用，我们获得了FOXP3-GFP敲入 老鼠。这些有价值的动物可用于分别研究 自然出现的Treg，以及抗原/细胞因子诱导的Treg的转化，扩展和功能。在 除这些动物外，其他资源包括MHC II类同种异体TCR转基因小鼠，MyD88- 不足的小鼠，并在所有这些菌株中交叉。 总的来说，这些研究将为差异化和命运提供重要的新见解 体内同种反应性T细胞，定义这些事件是如何通过炎症和抗原相遇调节的， 并探索方法可以通过调节性T细胞控制记忆T细胞反应。