Mechanisms of OX40 in peripheral transplant tolerance

描述（由申请人提供）：我们的目标是阐明OX 40（CD 134）（一种属于TNF-R超家族的新型共刺激分子）在T细胞活化和T细胞调节中的作用机制，以及靶向0X 40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OX 40调节移植排斥反应中一个关键但知之甚少的过程。已知0X 40在活化的T细胞上表达，但在静息的T细胞上不表达，并且0X 40信号支持细胞存活和增殖。然而，我们发现同种异体反应性的记忆T细胞和耐受诱导所需的CD 4 + Foxp 3 + T细胞组成性高水平表达OX 40。此外，我们有新的数据表明，OX 40定义了Foxp 3 + T细胞和T效应子的群体，这些OX 40细胞可以在过继转移模型中介导排斥或耐受，这取决于OX 40受体是被有意阻断还是被有意刺激。我们的新数据还表明，OX 40共刺激可以深刻地改变自然产生的CD 4 + CD 25 + T细胞的调节功能，并可以阻止激活的效应T细胞诱导新的Foxp 3 T细胞。基于这些发现，我们产生了以下假设：OX 40控制移植模型中调节型免疫应答发展的关键检查点。OX 40在促进强效应子和记忆型免疫中的显著作用可能阻断CD 4 + CD 25 + Foxp 3 + T细胞的调节功能或阻止从效应子库诱导新的诱导型Foxp 3 + T细胞。该假设将通过以下4个目标进行检验。目标1。为了检验以下假设：OX 40将天然FoxpS* T细胞重编程为非调节性和炎性表型，或者OX 40通过直接修改其生命和死亡程序而促凋亡为CD 4 * Foxp 3+天然T细胞。目标二。为了验证OX 40通过促进效应T细胞分化为Th 1/Th 2效应T细胞或记忆型T细胞来阻止新的诱导型Foxp 3 + T细胞的从头产生的假设。目标3。为了检验由OX 40共刺激指示的完全分化的效应/记忆T细胞对Foxp 3 +Treg介导的抑制具有高度抗性的假设。目标4。为了检验阻断0X 40/0X 40 L途径容易通过有利于调节型免疫应答而诱导显性移植耐受的假设，预期这些研究的完成将在开发新的治疗策略中提供关键的见解，所述新的治疗策略旨在在移植耐受的产生和某些自身免疫性疾病和癌症的治疗中操纵TCL 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.