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

在过去的几十年里，免疫抑制药物的进步大大提高了实体器官移植(SOT)中同种异体移植物的短期存活率。然而，长期功能的改善仍然是一个未达到的医学目标。由于可供移植器官的日益短缺，扩大标准供体(ECD)的边缘器官的利用已进入临床常规。供体年龄是定义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)是导致器官质量较差的因素。最近，我们发现人类衰老肾移植的特点是NK细胞相关的细胞毒受体NKG2D的高表达，这与移植肾功能低下有关。我们进一步证明，供者BD导致了固有淋巴细胞显著的器官特异性重新分布。随着先天淋巴样细胞(ILCs)的发现，这个家族已经有了相当大的扩展，ILCs是一组多方面的细胞，主要是组织驻留细胞，参与所需和不所需的免疫反应。在SOT的背景下，国际法委员会的作用迄今还没有得到全面的研究。我们的初步数据表明，潜在的再生性2型ILC(ILC2)存在于健康肾脏中，但在实验性肾移植后消失，而潜在的促炎NK细胞则填充在移植物中。我们进一步生成了第一个数据，指出ILC亚群在老年器官和年轻器官中的重新分布。在本项目中，我们将研究移植相关危险因素年龄、BD和IRI如何影响ILC生物学，以及这些危险因素诱导的ILC改变如何与同种异体移植的结果相关。由于SOT涉及供体和受体免疫的对峙，我们将通过研究供体和受体来源的ILC在同种异体移植物和远端器官中的迁移和存留来监测供体和受体来源的ILC在器官内的组成和功能。为了弄清供者或受者ILC的移植相关再分配是否与移植物功能改变有关，我们将从治疗上干预ILC的迁移能力，并分析移植物的结果。基于先前的研究表明IL-33和IL-25在肾损伤后的再生中的作用，我们将讨论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ILC2介导。我们的研究将通过分析移植前的人ILC样本以及器官修复机器灌流后的灌流液来补充。综上所述，我们将首次全面研究ILC在实体器官移植中的作用，并测试治疗上操纵ILC生物学以实现组织稳态和再生，从而改善移植物功能的策略。

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.