Mechanisms of OX40 in peripheral transplant tolerance

OX40在外周移植耐受中的机制

• 批准号: 7571677
• 负责人: Xian Chang Li
• 金额: $ 33.35万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571677
• 关键词: Adoptive Transfer; Allografting; Apoptosis; Apoptotic; Autoimmune Diseases; Cell Survival; Cells; Cessation of life; Chronic; Clinic; Data; Development; Generations; Goals; Graft Rejection; Immune response; Immunity; Immunosuppression; Inflammatory; Life; Malignant Neoplasms; Mediating; Memory; Modeling; Outcome; Pathway interactions; Peripheral; Phenotype; Play; Population; Process; Property; Research Personnel; Resistance; Rest; Role; Signal Transduction; Supporting Cell; T cell regulation; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF1A gene; Testing; Therapeutic; Time; Transplantation; base; insight; interest; novel therapeutics; prevent; programs; response; tumor necrosis factor receptor superfamily member 4

DESCRIPTION (provided by applicant): Our goal is to elucidate the mechanisms of action of OX40 (CD134), a new costimulatory molecule that belongs to the TNF-R superfamily, in T cell activation and T cell regulation, and the therapeutic implication of targeting 0X40 in the induction of transplant tolerance. This goal is based on our recent discovery that OX40 regulates a critical but poorly understood process in transplant rejection. It is known that OX40 is expressed on activated but not resting T cells, and 0X40 signals support cell survival and proliferation. However, we found that memory T cells that are alloreactive and the CD4+Foxp3+ Tregs that are required for tolerance induction constitutively express OX40 at high levels. Furthermore, we have new data showing that OX40 defines a population of Foxp3+ Tregs and T effectors, and these OX40 cells can either mediate rejection or tolerance in an adoptive transfer model depending on whether the OX40 receptor is intentionally blocked or deliberately stimulated. Our new data also showed that OX40 costimulation can profoundly alter the regulatory functions of naturally arising CD4+CD25+Tregs and can prevent the induction of new Foxp3 Tregs from activated effector T cells. Based on these findings, we generated the following hypothesis: OX40 controls a critical checkpoint in the development of a regulatory type of immune response in transplant models. The profound effects of OX40 in favoring a strong effector and memory types of immunity may block the regulatory functions of CD4+CD25+Foxp3+Tregs or prevent the induction of new inducible Foxp3+ Tregs from the effector pool. This hypothesis will be tested via the following 4 Aims. Aim# 1. To test the hypothesis that OX40 reprograms the natural FoxpS* Tregs to a non-regulatory and inflammatory phenotype or OX40 is pro-apoptotic to CD4*Foxp3+ natural Tregs by directly modifying their life and death programs. Aim # 2. To test the hypothesis that OX40 prevents de novo generation of new inducible Foxp3+ Tregs by promoting differentiation of effector T cells to Th1/Th2 effector T cells or to memory type of T cells. Aim #3. To test the hypothesis that fully differentiated effector/memory T cells instructed by OX40 costimulation are highly resistant to Foxp3+Treg mediated suppression. Aim # 4. To test the hypothesis that blocking the OX40/OX40L pathway readily induces dominant transplant tolerance by favoring a regulatory type of immune response It is anticipated that accomplishment of these studies will provide critical insights in the development of new therapeutic strategies aimed at manipulating Tregs in the creation of transplant tolerance and in the treatment of certain autoimmune diseases and cancers.

描述（由申请人提供）：我们的目标是阐明OX40（CD134）的作用机理，这是一种属于TNF-R超家族的新的共刺激分子，在T细胞激活和T细胞调节中，以及靶向0x40在诱导移植耐受的诱导中的治疗意义。该目标是基于我们最近发现的，即OX40调节移植排斥的关键但知之甚少的过程。众所周知，OX40在活化的T细胞上表示，而0x40信号支持细胞的存活和增殖。但是，我们发现具有同种异体反应性的记忆T细胞和耐受性诱导所需的CD4+ FOXP3+ Treg在高水平上组成型表达OX40。此外，我们有新的数据表明OX40定义了FOXP3+ Treg和T效应子的群体，并且这些OX40细胞可以根据有意阻止或有意刺激OX40受体在继承转移模型中介导反应或耐受性。我们的新数据还表明，OX40共刺激可以深刻地改变自然产生的CD4+CD25+Treg的调节功能，并可以防止从活化效应T细胞中诱导新的Foxp3 Treg。基于这些发现，我们产生了以下假设：OX40在移植模型中的调节类型的免疫反应的发展中控制着关键检查点。 OX40对有利于强效应子和免疫力的记忆类型的深远影响可能会阻止CD4+CD25+FOXP3+Tregs的调节功能，或者防止从效应库中诱导新的诱导型Foxp3+Treg。该假设将通过以下4个目标进行检验。目的＃1。为了测试OX40将天然FOXP* Treg重新编程为非调节和炎症表型或OX40的假说，通过直接修改其生死计划，对CD4* Foxp3+天然Treg是促凋亡的。目标＃2。通过促进效应T细胞与Th1/Th2效应T细胞或T细胞的记忆类型，通过促进效应T细胞的分化来阻止从头产生新的诱导Foxp3+ Treg的假说。目标＃3。为了检验以下假设：由OX40指示的完全分化的效应子/记忆T细胞对Foxp3+Treg介导的抑制具有高度抗性。目的4。为了检验以下假设：阻止OX40/OX40L途径很容易通过偏爱监管类型的免疫反应来引起主要的移植耐受性，预计这些研究的成就将在开发新的治疗策略方面提供关键的见解，该策略旨在在某些耐受范围内和在某些耐受的耐受性方面进行特雷格的范围，并在某些耐受性的耐受性方面进行了无效的治疗。