Mechanisms of TLR-mediated prevention of transplantation tolerance

TLR介导的移植耐受预防机制

基本信息

批准号：
8206674
负责人：
Maria-Luisa Alegre
金额：
$ 30.09万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): One major goal in transplantation immunology is to develop new immunosuppressive agents with the potential to induce donor-specific tolerance and thus avoid increased risk of infection and cancer in transplant recipients. Considerable effort has been spent on the study of costimulation-targeting therapies, as these regimens successfully induce permanent acceptance of tissues such as heart grafts and pancreatic islets in rodents. However, we and others have recently shown that infections at the time of transplantation potently antagonize the ability of costimulation-blockade therapies to achieve donor-specific tolerance. Microorganisms contain molecular patterns that are recognized by Toll-like receptors (TLRs) expressed on host and donor cells. Our results indicate that engagement of a single TLR at the time of cardiac transplantation is sufficient to prevent graft acceptance induced by anti-CD154 donor-specific transfusion (DST) or CTLA-4-Ig in mice. Understanding the mechanisms by which TLR signaling opposes pathways of transplantation tolerance is essential to develop novel therapies likely to be successful in the clinic, in patients constantly exposed to both commensal and pathogenic microorganisms. Induction and maintenance of cardiac transplantation tolerance by anti-CD154/DST is known to depend on regulatory T cells (Tregs). We have shown that anti-CD154 promotes intragraft accumulation of Tregs and development of dominant regulation in the form of linked-suppression. These phenomena are both antagonized by the TLR9 agonist CpG-B. Our preliminary results have shown that CpG prevents Treg recruitment to cardiac allografts and inhibits the ability of anti-CD154 to achieve a high Treg to effector T cell (Teff) ratio in the graft. Treg:Teff ratio in target tissues is emerging as a critical parameter controlling the outcome of immune responses in vivo, but signals determining this ratio are not well understood. Our results support the central hypothesis that TLR signaling controls the Treg/Teff ratio in the allograft and the consequent fate of transplanted organs. Our preliminary results suggest there may be effects of TLR signaling on both Tregs and Teffs. In this application, we will study the mechanisms by which TLR signaling opposes transplantation tolerance. This will be performed in the context of the following specific aims. Specific Aim 1. To investigate the mechanisms by which CpG limits intragraft Treg accumulation during prevention of transplantation tolerance. Specific Aim 2. To delineate nTreg-independent effects of TLR signaling on graft-reactive Teffs and APCs during the prevention of transplantation tolerance. Completion of these aims should reveal new consequences of TLR signaling in vivo and should yield a deeper understanding of different facets of the interplay between innate and adaptive immune responses that may negatively impact establishment of transplantation tolerance. Project Narrative: The interplay between innate and adaptive immune system determines the fate of an immune response. We have recently shown that microbial products that signal via toll-like receptors (TLRs) can prevent the induction of transplantation tolerance. In this application, we propose to investigate the mechanisms by which TLR signaling antagonizes tolerogenic signals.

描述（由申请人提供）：移植免疫学的一个主要目标是开发新的免疫抑制剂，有可能诱导供体特异性耐受性，从而避免增加移植受者感染和癌症的风险增加。在靶向靶向疗法的研究上已经花费了大量努力，因为这些方案成功地引起了对啮齿动物中心脏移植和胰岛等组织的永久接受。但是，我们和其他人最近表明，移植时的感染有效地拮抗了结肠刺激阻挡疗法实现供体特异性耐受性的能力。微生物包含分子模式，这些模式由在宿主和供体细胞上表达的Toll样受体（TLR）识别。我们的结果表明，心脏移植时单个TLR的参与足以防止抗CD154供体特异性输血（DST）或CTLA-4-Ig在小鼠中引起的移植物接受。了解TLR信号与移植耐受性相反的机制对于开发可能在诊所中成功的新型疗法至关重要，在不断暴露于共生和致病性微生物的患者中。已知抗CD154/DST诱导和维持心脏移植耐受性取决于调节性T细胞（Tregs）。我们已经表明，抗CD154促进了Tregs的内部积累，并以连接抑制的形式促进了主导调节的发展。这些现象都被TLR9激动剂CpG-B拮抗。我们的初步结果表明，CPG可防止Treg募集对心脏同种异体移植物，并抑制抗CD154在移植物中实现高Treg与效应T细胞（TEFF）比率的能力。 Treg：目标组织中的TEFF比率是控制体内免疫反应结果的关键参数，但是确定该比率的信号尚不清楚。我们的结果支持了一个中心假设，即TLR信号控制同种异体移植物和随之而来的移植器官命运的Treg/Teff比。我们的初步结果表明，TLR信号可能对Treg和Teffs产生影响。在此应用中，我们将研究TLR信号反对移植耐受性的机制。这将在以下特定目的的背景下执行。具体目的1。研究CpG在预防移植耐受期间限制内部Treg积累的机制。具体目的2。描述TLR信号在预防移植耐受性期间对移植反应性TEFF和APC的非依赖性效应。这些目标的完成应揭示体内TLR信号传导的新后果，并应对先天和适应性免疫反应之间相互作用的不同方面有更深入的了解，这可能会对移植耐受的建立产生负面影响。项目叙述：先天和适应性免疫系统之间的相互作用决定了免疫反应的命运。我们最近表明，通过Toll样受体（TLR）发出信号的微生物产物可以防止诱导移植耐受性。在此应用中，我们建议研究TLR信号传导拮抗耐受性信号的机制。