Role of Innate Lymphoid Cells (ILC) in Solid Organ Transplantation

先天淋巴细胞 (ILC) 在实体器官移植中的作用

• 批准号: 428193823
• 负责人: Professorin Dr. Katja Kotsch, Ph.D.
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Gefäßchirurgie (CBF)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428193823?language=en
• 关键词: Role; Innate; Lymphoid; Cells; ILC

Over the past decades the progress in immunosuppressive medication resulted in substantial improvement of short-term allograft survival in solid organ transplantation (SOT). However, an improvement of long-term function is still an unmet medical goal. Due to the progressing shortage of available transplants, the utilization of marginal organs from expanded criteria donors (ECD) has been implemented into clinical routine. Donor age is the most important risk factor defining an ECD organ, with donor brain death (BD) and ischemia-reperfusion injury (IRI) representing contributing factors for inferior organ quality. Recently, we demonstrated that human senescent kidney grafts are characterized by high expression of the NK-cell-associated cytotoxicity receptor NKG2D, being associated with inferior graft function. We further demonstrated that donor BD results in a significant organ-specific redistribution of innate lymphocytes. This family has considerably expanded with the discovery of innate lymphoid cells (ILCs), a multifaceted group of mainly tissue resident cells involved in desired and undesired immune responses. In the context of SOT, the role of ILC has not been comprehensively studied so far. Our preliminary data demonstrate that potentially regenerative type2 ILC (ILC2) reside within the healthy kidney, but disappear after experimental kidney transplantation, whereas potentially pro-inflammatory NK cells populate the graft. We further generated first data pointing towards a redistribution of ILC subsets in aged versus young organs. In the present project, we will examine how ILC biology is impacted by the transplantation-associated risk factors age, BD and IRI and how these risk factor induced ILC alterations relate to allograft outcome. As SOT entails the confrontation of both donor and recipient immunity, we will monitor the intra-organ composition and function of both donor- and recipient-derived ILCs by studying their migration to and persistence in the allograft as well as to distal organs. To decipher whether the transplantation-associated redistribution of donor or recipient ILCs is associated with altered graft function, we will therapeutically interfere with ILC migration capacity and analyse graft outcome. Based on previous studies suggesting a role for Interleukin-33 and Interleukin-25 in the regeneration following kidney damage, we will address whether treatment of the donor or recipient can reduce tissue injury post-transplantation and whether this process is mediated by regenerative ILC2. Our studies will be complemented by the analysis of human ILC samples before transplantation as well as in perfusates following machine perfusion for organ reconditioning. In summary, we will for the first time comprehensively study the role of ILC in the context of solid organ transplantation and test strategies to therapeutically manipulate ILC biology towards tissue homeostasis and regeneration, thereby improving graft function.

在过去的几十年中，免疫抑制剂的进展导致实体器官移植（SOT）中短期同种异体移植物存活率的显著改善。然而，长期功能的改善仍然是一个未满足的医疗目标。由于可供移植器官的日益短缺，来自扩展标准供体（ECD）的边缘器官的利用已成为临床常规。供体年龄是决定ECD器官的最重要的危险因素，供体脑死亡（BD）和缺血再灌注损伤（IRI）是导致器官质量低下的因素。最近，我们证明，人衰老的肾移植的特点是高表达的NK细胞相关的细胞毒性受体NKG 2D，与劣质移植功能。我们进一步证明，供体BD会导致先天淋巴细胞显着的器官特异性再分布。该家族随着先天性淋巴样细胞（ILC）的发现而大大扩展，所述先天性淋巴样细胞是参与期望的和不期望的免疫应答的主要组织驻留细胞的多面组。在SOT的背景下，国际法委员会的作用迄今尚未得到全面研究。我们的初步数据表明，潜在的再生2型ILC（ILC 2）驻留在健康肾脏内，但在实验性肾移植后消失，而潜在的促炎NK细胞填充移植物。我们进一步生成了第一个数据，指向老年与年轻器官中ILC亚群的重新分布。在本项目中，我们将研究ILC生物学如何受到移植相关风险因素年龄、BD和IRI的影响，以及这些风险因素诱导的ILC改变如何与同种异体移植结局相关。由于SOT需要供体和受体免疫的对抗，我们将通过研究供体和供体来源的ILC迁移到同种异体移植物和远端器官中的持久性来监测它们的器官内组成和功能。为了解释供体或受体ILC的移植相关再分布是否与移植物功能改变相关，我们将治疗性干扰ILC迁移能力并分析移植物结局。基于之前的研究表明白细胞介素-33和白细胞介素-25在肾脏损伤后的再生中发挥作用，我们将研究供体或受体的治疗是否可以减少移植后的组织损伤，以及这一过程是否由再生的ILC 2介导。我们的研究将通过分析移植前的人ILC样本以及机器灌注后的灌注液进行器官修复来补充。总之，我们将首次全面研究ILC在实体器官移植中的作用，并测试策略以治疗性地操纵ILC生物学以实现组织稳态和再生，从而改善移植物功能。