Inducing Stably Persistent Transplantation Tolerance: A Mechanistic Perspective

诱导稳定持久的移植耐受：机制视角

• 批准号: 8683092
• 负责人: Maria-Luisa Alegre
• 金额: $ 39.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8683092
• 关键词: Acute; Allografting; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Clinic; Clinical; Control Animal; Development; Genetic Variation; Human; IL2RA gene; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Inflammatory; Listeria monocytogenes; Maintenance; Measures; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Predisposition; Prevention; Process; Reagent; Regimen; Regulation; Regulatory T-Lymphocyte; Resistance; Rodent; Role; Signal Transduction; Specific Pathogen Frees; Stimulus; T cell anergy; T cell regulation; T-Cell Depletion; T-Lymphocyte; TNFSF5 gene; Tamoxifen; Testing; Therapeutic immunosuppression; Transplantation; Transplantation Tolerance; allograft rejection; anergy; clinically relevant; exhaustion; germ free condition; heart allograft; in vivo; insight; isoimmunity; prevent; research study; response; transcription factor

Donor-specific transplantation tolerance, as defined by graft acceptance after discontinuation of immunosuppressive therapies, can be achieved in specific pathogen-free rodents but rarely in humans. Deletion, anergy and suppression of alloreactive T cells are 3 cellular mechanisms most often associated with the induction of transplantation tolerance in mice. It has been shown that deletion of alloreactive T cells and suppression of remaining alloreactive T cells by CD25* regulatory T cells (Tregs) are necessary for the induction of transplantation tolerance by costimulation blockade. However, whether T cell anergy is necessary and/or sufficient for the induction and/or the maintenance of transplantation tolerance is not known. Furthermore, it is not clear if these 3 mechanisms of T cell tolerance (and others potentially) need to be coinduced simultaneously for tolerance to be robust and maintained long-term successfully. If they do need to be co-induced, the usual lack of development of transplantation tolerance in humans could be due to the inability of current immunosuppressive regimens to induce/maintain these 3 pathways concurrently. Our preliminary experiments indicate that tolerance is not an all or none phenomenon and that a readout of allograft acceptance is not a sensitive measure of the functional robustness of transplantation tolerance. Indeed, we observed that depletion of Tregs or blockade of PD-L1 does not abrogate established tolerance, but is able to precipitate acute cardiac allograft rejection in tolerant mice that had been previously infected with Listeria monocytogenes but retained their graft. This suggests that the quality or quantity of mechanisms that maintain graft acceptance are modified after infection and that a simple lack of acute rejection does not inform on the stability of the tolerant state or how close the alloimmune response is to the rejection threshold. We propose that "transplantation tolerance" is a continuum of states in which the number and intensity of anti-inflammatory processes that constrain alloimmunity are progressively eroded by pro-inflammatory signals (infectious episodes or others) until a rejection threshold is reached. Although intuitive, this concept has not been investigated in any systematic manner and has important implications in clinical transplantation: it may explain why patients who achieve transplantation tolerance, i.e., years of stable function without immunosuppressive drugs, or even patients stably maintained with minimal immunosuppression, may suddenly reject their grafts; the robustness of the tolerance level may also determine whether immunosuppressive drugs can be withdrawn and whether tolerance can persist. We specifically hypothesize that a state of transplantation tolerance that Is robust and that can persist and resist Inflammatory insults may only be achieved when T cell depletion, T cell regulation and T cell anergy are all co-induced simultaneously and optimally. Insights gained from these mechanistic analyses will be of importance in the clinic, where the genetic diversity of the transplant population all but guarantees that individuals receiving the same treatment will develop different degrees of deletion, anergy and suppression. This hypothesis will be tested in the context of the following specific aims: Aim 1: To determine the requirement for T cell anergy in the induction and maintenance of transplantation tolerance. Aim 2: To assess the necessity and sufficiency of T cell mechanisms of tolerance in the establishment of robust transplantation tolerance.

供体特异性移植耐受性，如停药后的接枝接受所定义 免疫抑制疗法可以在特定的无病原体啮齿动物中实现，但很少在人类中。 缺失，反应和抑制同种异体T细胞是最常与的​​3个细胞机制 小鼠移植耐受性的诱导。已经表明，同种反应性T细胞的缺失和 CD25*调节T细胞（TREG）抑制剩余的同种异体T细胞是必要的 通过共刺激阻滞诱导移植耐受性。但是，是否需要T细胞消极 和/或足以诱导和/或维持移植耐受性。 此外，尚不清楚是否需要对这三种T细胞耐受性（以及其他可能的）机理进行诱导 同时宽容可以保持稳健，并成功地保持了长期。如果他们确实需要 共同引起的，通常缺乏人类移植耐受性的发展可能是由于无法 当前的免疫抑制方案同时诱导/维持这3条途径。 我们的初步实验表明，公差不是全部或没有现象，而是读数 同种异体的接受度不是对移植耐受性功能鲁棒性的敏感度量。 确实，我们观察到，dregs的耗竭或PD-L1的阻滞不会消除确定的耐受性， 但能够在先前感染的耐受小鼠中沉淀急性心脏同种异体移植排斥 单核细胞增生李斯特菌，但保留了移植物。这表明机制的质量或数量 感染后维持移植物接受是修改的，并且简单缺乏急性拒绝并不能告知 关于耐受状态的稳定性或同种免疫反应的距离与排斥阈值有多近。 我们建议“移植公差”是数量和强度的连续性状态 限制同种免疫性的抗炎过程被促炎性侵蚀 信号（感染性发作或其他发作），直到达到拒绝阈值。尽管直观，但这个概念 尚未以任何系统的方式研究，并且对临床移植具有重要意义： 可以解释为什么实现移植耐受性的患者，即，稳定的功能稳定的患者 免疫抑制药物，甚至是稳定维持的免疫抑制的患者，可能 突然拒绝他们的移植物；公差水平的鲁棒性也可能决定 可以撤回免疫抑制药物，并且耐受性是否可以持续。 我们特别假设一种稳健的移植耐受状态，可以持续存在 只有当T细胞耗竭，T细胞调节和T细胞消极时，才能抵抗炎症性损伤 都是同时且最佳的共同引起的。从这些机械分析中获得的见解将是 在诊所中的重要性，移植人群的遗传多样性几乎保证 接受相同治疗的个体将产生不同程度的缺失，不反应和抑制。 该假设将在以下特定目的的背景下进行检验：目标1：确定要求 用于T细胞消除移植耐受性的诱导和维持。目标2：评估必要性 T细胞机制的足够耐受性在建立稳健移植耐受性中。