Role of Tissue-Resident Leukocytes in the Kidney – Implications for Allograft Survival According to Age

在全球范围内，到2050年，60岁及以上的人口数量将从占人口的12%增加到约22%。人口结构的发展以及总体上缺乏合适的供体器官导致所谓的扩大标准供体器官（ECD）的使用增加。由于这些器官显示出受限制的同种异体移植存活，因此了解排斥反应的潜在免疫机制对于通过治疗干预提高衰老器官的长期存活具有普遍的重要性。我们已经证明，生物标志物NKG2D（一种激活受体）在活组织检查中的鉴定可以预测肾脏衰老的结果。此外，我们还发现，用抗淋巴细胞球蛋白多克隆抗体对肾脏进行围手术期调理可以改善移植物功能。原则上，衰老免疫系统的标志是naïve T细胞的下降与克隆扩增效应/记忆T细胞的增加并行。然而，最近已经证明，大多数CD8+记忆T细胞并不存在于外周，而是存在于肠道、肺和皮肤中，在那里它们通过快速产生效应分子来促进局部保护性免疫反应。目前尚不清楚的是，这些长寿和组织驻留的T细胞是如何在衰老过程中被修改的，以及它们是如何导致实体器官（如肾脏）的排斥反应的。肾脏是世界上最常见的移植器官。我们在异基因小鼠肾移植模型中的初步数据表明，受体来源的T细胞在移植后不久迁移到器官中，获得以整合素CD103和组织保留标记CD69表达为特征的组织驻留表型。通过分析切除的人肾脏，我们还证明了内源性的、组织驻留的CD103+CD69+ T细胞可以被识别出来。此外，这些来自老年肾脏的细胞显示出cd28缺失表型，这与更高的炎症潜力相关。因此，在特别考虑风险因素年龄的情况下，本研究的目的是(i)表征肾脏中内源性组织常驻记忆T细胞，（ii）分析其炎症潜能、抗原特异性、克隆性和代谢，（iii）检查同种异体移植物中组织常驻记忆的产生，（iv）调节或消耗这些细胞以延长同种异体移植物的存活时间。

Throughout the world, the number of individuals aged 60 years and older will increase to from 12% to approximately 22% of the population by 2050. Both, this demographic development together with the overall lack of suitable donor organs result in the increased usage of so-called expanded criteria donor organs (ECD). As these organs illustrate restricted allograft survival, it is of general importance to understand the underlying immunological mechanisms of rejection in order to improve the long term survival of senescent organs by therapeutic interventions. We already demonstrated that the identification of the biomarker NKG2D, an activating receptor, in biopsies is predictive for the outcome of senescent kidneys. In addition, we showed that the peri-operative conditioning of kidneys with the polyclonal antibody anti-lymphocyte globulin results in an improved graft function. In principle, the hallmark of a senescent immune system is characterized by a decline of naïve T cells parallel with an increase of clonally expanded effector/memory T cells. However, it has been demonstrated recently, that the majority of CD8+ memory T cells is not present in the periphery but reside in the intestine, lung and skin where they contribute to a local protective immune response by the rapid generation of effector molecules. It is not clarified yet, how this pool of long-living and tissue-resident T cells is modified during ageing and how it contributes to the rejection of solid organs such as kidney, the most frequent transplanted organ worldwide. Our preliminary data in an allogeneic murine kidney transplantation model illustrate, that recipient-derived T cells migrate into the organ shortly after transplantation, acquiring a tissue resident phenotype characterized by the expression of the integrin CD103 and the tissue retention marker CD69. By analysing resected human kidneys, we additionally demonstrate that endogenous, tissue-resident CD103+CD69+ T cells can be identified. Moreover, these cells derived from aged kidneys illustrate a CD28null phenotype, which is associated with a higher inflammatory potential. The aims of the study are therefore, under the special consideration of the risk factor age, to (i) characterize endogenous tissue-resident memory T cells in the kidney, to (ii) analyse their inflammatory potential, antigen specificity, clonality and metabolism, to (iii) examine the generation of tissue-resident memory in the allograft and to (iv) modulate or deplete these cells in order to prolong allograft survival.