T cell activation death & memory in alloimmune responses
T细胞活化死亡
基本信息
- 批准号:7009366
- 负责人:
- 金额:$ 42.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-03-15 至 2010-05-31
- 项目状态:已结题
- 来源:
- 关键词:CD28 moleculeMHC class II antigenSCID mouseT cell receptorathymic mousecell deathcytotoxic T lymphocyteflow cytometrygenetically modified animalsheart transplantationhelper T lymphocytehomologous transplantationimmune responseimmune tolerance /unresponsivenessimmunologic memoryleukocyte activation /transformationlymphocyte proliferationlymphopeniamonoclonal antibodypassive immunizationsirolimustransplant rejectiontransplantation immunology
项目摘要
DESCRIPTION (provided by applicant): The long-term goal of this program is to use murine transplantation models to address mechanistic questions about requirements for, and barriers to, tolerance. Despite great advances, very few strategies induce reproducible tolerance in stringent mouse models and in primates. Therefore, in this competing renewal for a third funding period, our goals are to define mechanisms of resistance to tolerance, and to develop strategies to overcome them for translation in stringent model, in primates and ultimately humans.
Why is tolerance in stringent systems (e.g., skin, large animals) so hard to achieve? Studies from our lab and others using peripheral (i.e., non-bone marrow/thymic) approaches to induce tolerance, have shown that: (1) It is relatively easy to induce long-term graft survival/tolerance in mice harboring only naive T cells; (2) Both deletion and the induction of regulatory cells play key roles in this process; and (3) Memory cells, existing due to specific immunization, heterologous immunity, or as a result of homeostatic proliferation following non-specific T cell depletion, are a potent barrier to tolerance. Based on these findings, our overall theoretical framework is that primary barriers to tolerance are resistance to death by effector/memory T cells, and defects in the homeostasis and/or function of regulatory T cells. We believe we now have the necessary tools and models in hand to formulate and test specific hypothesis predicted by this framework. Aim #1 will determine why homeostatic proliferation is a barrier to tolerance. We will test the hypotheses that this barrier is the result of the differential susceptibility of naive T cells, memory T cells, and regulatory T cells to undergo deletion by anti-T cell reagents, and their subsequent ability to "recover" via homeostatic proliferation, under conditions of lymphopenia. Aim #2 will test the susceptibility of memory CD4 T cells to death and regulation. Using a TCR transgenic MHC class II alloreactive CD4 T cell system, we will examine two separate hypotheses, namely that memory T cells are more resistant to death (hypothesis 1) and to regulation (hypothesis 2) than their naive counterparts. Aim #3 will determine whether defects in immunoregulation are mechanisms of tolerance resistance. Using alloreactive CD4+ TCR transgenic mice we will test the hypothesis that failure to acquire or maintain tolerance is due to lack of regulation, relating to either the antigen specificity of the regulatory cell generated, the availability, or lack thereof, of indirect allorecognition, the inherent immunogenicity of selected tissues/organs, and the degree of antigenic disparity between donor and recipient. These studies to define mechanisms of resistance to tolerance in defined clinically relevant models should help in developing novel approaches to induce tolerance in humans.
描述(由申请人提供):该计划的长期目标是使用小鼠移植模型来解决有关耐受性要求和障碍的机制问题。尽管取得了巨大进步,但很少有策略在严格的小鼠模型和灵长类动物中诱导可重复的耐受性。因此,在第三个资助期的竞争更新中,我们的目标是定义耐受性的抵抗机制,并制定克服这些机制的策略,以便在灵长类动物和最终人类的严格模型中进行翻译。
为什么严格系统(例如皮肤、大型动物)的耐受性如此难以实现?我们实验室和其他实验室使用外周(即非骨髓/胸腺)方法诱导耐受性的研究表明:(1) 在仅含有初始 T 细胞的小鼠中诱导长期移植物存活/耐受性相对容易; (2)调节细胞的缺失和诱导在此过程中均发挥关键作用; (3) 由于特异性免疫、异源免疫或非特异性 T 细胞耗竭后的稳态增殖而存在的记忆细胞是耐受性的有效屏障。基于这些发现,我们的总体理论框架是,耐受性的主要障碍是效应/记忆 T 细胞对死亡的抵抗力,以及调节性 T 细胞的稳态和/或功能缺陷。我们相信,我们现在拥有必要的工具和模型来制定和测试该框架预测的具体假设。目标#1 将确定为什么稳态增殖是耐受性的障碍。我们将测试这一假设,即这种屏障是由于幼稚 T 细胞、记忆 T 细胞和调节性 T 细胞对抗 T 细胞试剂删除的不同敏感性以及它们随后通过稳态增殖“恢复”的能力造成的。在淋巴细胞减少的情况下。目标 #2 将测试记忆 CD4 T 细胞对死亡和调节的敏感性。使用 TCR 转基因 MHC II 类同种异体反应性 CD4 T 细胞系统,我们将检查两个独立的假设,即记忆 T 细胞比其原始对应细胞更能抵抗死亡(假设 1)和调节(假设 2)。目标#3 将确定免疫调节缺陷是否是耐受性抵抗的机制。使用同种异体反应性 CD4+ TCR 转基因小鼠,我们将测试以下假设:未能获得或维持耐受性是由于缺乏调节,与生成的调节细胞的抗原特异性、间接同种异体识别的可用性或缺乏相关,固有的所选组织/器官的免疫原性,以及供体和受体之间抗原差异的程度。这些在明确的临床相关模型中定义耐受耐受机制的研究应有助于开发诱导人类耐受的新方法。
项目成果
期刊论文数量(0)
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Laurence A Turka其他文献
Plus ça change, plus c'est la même chose.
再加上改变,再加上我选择了。
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:15.9
- 作者:
Laurence A Turka - 通讯作者:
Laurence A Turka
Solid organ transplantation: solid but not yet spectacular
实体器官移植:扎实但尚未引人注目
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:15.9
- 作者:
Laurence A Turka - 通讯作者:
Laurence A Turka
Laurence A Turka的其他文献
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{{ truncateString('Laurence A Turka', 18)}}的其他基金
Control of Treg Homeostasis and Function by the Lipid Phosphatase PTEN
脂质磷酸酶 PTEN 对 Treg 稳态和功能的控制
- 批准号:
8489869 - 财政年份:2013
- 资助金额:
$ 42.62万 - 项目类别:
Control of Treg Homeostasis and Function by the Lipid Phosphatase PTEN
脂质磷酸酶 PTEN 对 Treg 稳态和功能的控制
- 批准号:
8722954 - 财政年份:2013
- 资助金额:
$ 42.62万 - 项目类别:
The Control of T Cell Development in Responses by PTEN
PTEN 对 T 细胞发育反应的控制
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8311931 - 财政年份:2011
- 资助金额:
$ 42.62万 - 项目类别:
Regulation, Memory and Inflammation in Transplantation
移植中的调节、记忆和炎症
- 批准号:
7644027 - 财政年份:2008
- 资助金额:
$ 42.62万 - 项目类别:
Regulation, Memory and Inflammation in Transplantation
移植中的调节、记忆和炎症
- 批准号:
7338985 - 财政年份:2007
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$ 42.62万 - 项目类别:
Expression and function of the TLRs on T cells
T 细胞上 TLR 的表达和功能
- 批准号:
7273901 - 财政年份:2006
- 资助金额:
$ 42.62万 - 项目类别:
Expression and function of the TLRs on T cells
T 细胞上 TLR 的表达和功能
- 批准号:
7162068 - 财政年份:2006
- 资助金额:
$ 42.62万 - 项目类别:
Expression and function of the TLRs on T cells
T 细胞上 TLR 的表达和功能
- 批准号:
7544542 - 财政年份:2006
- 资助金额:
$ 42.62万 - 项目类别:
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