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

肾脏中组织驻留白细胞的作用 â 对不同年龄的同种异体移植物存活的影响

• 批准号: 421576852
• 负责人: Professorin Dr. Katja Kotsch, Ph.D.
• 金额: --
• 依托单位: Klinik für Urologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/421576852?language=en
• 关键词: Role; Tissue; Resident; Leukocytes; Kidney

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.

到2050年，全世界60岁及以上的人口数量将从人口的12%增加到约22%。这两种情况，人口统计学的发展加上整体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。由于这些器官说明了有限的同种异体移植物存活，因此了解排斥反应的潜在免疫机制以通过治疗干预改善衰老器官的长期存活具有普遍重要性。我们已经证明，在活检中鉴定生物标志物NKG 2D（一种活化受体）可预测衰老肾脏的结局。此外，我们发现，围手术期用多克隆抗体抗淋巴细胞球蛋白调节肾脏可改善移植肾功能。原则上，衰老免疫系统的特征在于幼稚T细胞的下降与克隆扩增的效应/记忆T细胞的增加平行。然而，最近已经证明，大多数CD 8+记忆T细胞不存在于外周中，而是存在于肠、肺和皮肤中，在那里它们通过快速产生效应分子而有助于局部保护性免疫应答。目前还不清楚，这种长寿和组织驻留的T细胞池在衰老过程中如何被修改，以及它如何有助于对实体器官（如肾脏）的排斥反应，这是世界上最常见的移植器官。我们在同种异体小鼠肾移植模型中的初步数据说明，移植后不久，免疫原性衍生的T细胞迁移到器官中，获得以整合素CD 103和组织滞留标记物CD 69的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CD 103 + CD 69 + T细胞可以被识别。此外，这些来源于老化肾脏的细胞显示了CD 28无效表型，这与更高的炎症潜能相关。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）表征肾脏中的内源性组织驻留记忆T细胞，（ii）分析其炎症潜力、抗原特异性、克隆性和代谢，（iii）检查同种异体移植物中组织驻留记忆的产生，以及（iv）调节或耗尽这些细胞以延长同种异体移植物存活。