Mechanisms of OX40 in peripheral transplant tolerance

描述(申请人提供)：我们的目标是阐明OX40(CD134)，一种属于肿瘤坏死因子受体超家族的新的共刺激分子，在T细胞激活和T细胞调节中的作用机制，以及靶向0X40在诱导移植耐受中的治疗意义。这一目标是基于我们最近的发现，即OX40调节移植排斥反应中的一个关键但知之甚少的过程。已知OX40表达在激活的T细胞上，而不是静止的T细胞上，0X40信号支持细胞的存活和增殖。然而，我们发现，同种异体反应的记忆T细胞和耐受诱导所需的CD4+Foxp3+Tregs结构性地高水平表达OX40。此外，我们有新的数据表明，OX40定义了一组Foxp3+Tregs和T效应器，这些OX40细胞可以在过继转移模型中介导排斥或耐受，这取决于OX40受体是被故意阻断还是被故意刺激。我们的新数据还表明，OX40共刺激可以深刻改变自然产生的CD4+CD25+Tregs的调节功能，并可以阻止新的Foxp3Tregs从激活的效应器T细胞中诱导出来。基于这些发现，我们产生了以下假设：OX40控制着移植模型中调节型免疫反应发展的关键检查点。OX40在支持强大的效应器和记忆类型免疫方面的深刻影响可能会阻断CD4+CD25+Foxp3+Tregs的调节功能或阻止新的可诱导的Foxp3+Tregs从效应池中诱导出来。这一假设将通过以下四个目标进行检验。目的#1.通过直接修改天然FoxpS*Tregs的生死程序，验证OX40将天然FoxpS*Tregs重新编程为非调节性和炎症性表型，或者OX40通过直接修改其生命和死亡程序促进CD4*Foxp3+天然Tregs凋亡的假设。目的#2.验证OX40通过促进效应T细胞分化为Th1/Th2效应T细胞或向记忆型T细胞分化而阻止新的可诱导Foxp3+Tregs从头产生的假设。目的#3.验证OX40共刺激诱导的完全分化效应/记忆T细胞对Foxp3+Treg介导的抑制具有高度抵抗力的假设。目的#4.为了验证阻断OX40/OX40L通路容易通过有利于调节类型的免疫反应而诱导显性移植耐受的假设，预计这些研究的完成将为开发新的治疗策略提供关键的见解，旨在操纵Tregs在创造移植耐受和治疗某些自身免疫性疾病和癌症方面的作用。

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.