Regulation, Memory and Inflammation in Transplantation

移植中的调节、记忆和炎症

基本信息

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
项目类别：
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

项目摘要

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“相对”容易，但相同的方法事实证明，很难将其转化为更大的动物和患者。原因之一是小动物模型通常无法考虑内存障碍。除了这个已知的障碍之外，越来越多的证据表明炎症（可能由于排斥、缺血再灌注损伤、感染而发生）等）也可以抑制耐受诱导。该项目的中心原则是在植入过程中发生的两个事件，炎症和抗原相遇，可以通过调节来确定移植结果和耐受性易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引发了调节和效应器/记忆发育之间的“竞赛”或“竞争”，并且这一结果对于移植的结果至关重要。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，同时抑制监管（目标#1）；除了其对效应器/记忆发育的已知影响之外，抗原遭遇也塑造了 Treg 的发展（目标#2），以及在以下情况下“功能失调”的调节：如果使用辅助方法，仍然可以利用记忆来阻止记忆反应（目的＃3）。这项工作对于项目#1 的研究非常重要，特别是那些关注如何 TIM1:TIM4 通路影响 Treg 的生成和转化。 .还将与您进行近距离互动项目#3，特别是在细胞因子和炎症如何相互作用影响记忆和记忆领域调节，以及共刺激封锁如何影响这些过程。我们带来了许多对这些研究至关重要的重要工具。通过我们不断的作为 PPG 的一部分，与 Terry Strom 和 Mo Sayegh 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单独研究自然产生的 Tregs，以及抗原/细胞因子诱导的 Tregs 的转化、扩增和功能。在除了这些动物之外，其他资源还包括 MHC II 类同种异体反应性 TCR 转基因小鼠、MyD88- 有缺陷的小鼠，并在所有这些品系之间进行杂交。总的来说，这些研究将为人类的分化和命运提供重要的新见解。体内同种异体反应性 T 细胞，定义这些事件如何通过炎症和抗原相遇来调节，并探索通过调节性 T 细胞控制记忆 T 细胞反应的方法。