T cell activation death & memory in alloimmune responses

T细胞活化死亡

• 批准号: 6919591
• 负责人: Laurence A Turka
• 金额: $ 36.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/6919591
• 关键词: CD28 molecule; MHC class II antigen; SCID mouse; T cell receptor; athymic mouse; cell death; cytotoxic T lymphocyte; flow cytometry; genetically modified animals; heart transplantation; helper T lymphocyte; homologous transplantation; immune response; immune tolerance /unresponsiveness; immunologic memory; leukocyte activation /transformation; lymphocyte proliferation; lymphopenia; monoclonal antibody; passive immunization; sirolimus; transplant rejection; transplantation immunology

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鼠类移植模型来解决有关公差要求和障碍的机械问题。尽管取得了长足的进步，但很少有策略在严格的小鼠模型和灵长类动物中引起可重复的耐受性。因此，在第三个融资期间的这种竞争续约中，我们的目标是定义对宽容的抵抗机制，并制定战略以克服它们以在灵长类动物和最终人类中的严格模型中翻译而克服它们。 为什么在严格的系统（例如，皮肤，大动物）中如此难以实现的耐受性？我们实验室和其他使用周围的研究（即非骨髓/胸腺）诱导耐受性的研究表明：（1）仅诱导只有天真T细胞的小鼠的长期移植物存活/耐受性相对容易； （2）缺失和调节细胞的诱导在此过程中起着关键作用； （3）由于特异性免疫，异源免疫或由于非特异性T细胞耗竭后的稳态增殖而导致的记忆细胞是耐受性的有效障碍。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子/记忆T细胞对死亡的抵抗，以及调节性T细胞的稳态和/或功能的缺陷。我们认为，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特定假设。 AIM＃1将确定为什么体内平稳性扩散是公差的障碍。我们将检验以下假设：该障碍是幼稚T细胞，记忆T细胞和调节性T细胞的差异敏感性，以通过抗T细胞试剂进行缺失，以及随后在淋巴细胞减少症的情况下通过体内稳态增殖“恢复”的能力。 AIM＃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细胞对死亡更具抵抗力（假设1）和调节（假设2）（假设2）。 AIM＃3将确定免疫调节中的缺陷是否是耐受性的机制。 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.这些研究定义了定义的临床相关模型中对耐受性的耐药性机制，应有助于开发新的方法来诱导人类的耐受性。