Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.
Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.
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DOI：
10.3389/fimmu.2023.1139358
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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肾移植受者目前接受非特异性免疫抑制剂治疗，导致严重的全身副作用。目前的免疫抑制剂是基于其对T细胞活化的影响而开发的，而不是驱动同种免疫反应的潜在机制。因此，了解移植物内微环境的作用将有助于我们确定更有针对性的治疗方法，降低副作用。为了了解同种免疫反应和移植物内微环境在细胞排斥进展中的作用，我们对一个人非排斥性肾移植物样本、一个临界样本和T细胞介导的排斥（TCMR）样本（Banff IIa）进行了单核RNA测序（snRNA-seq）。我们研究了不同条件下基因的差异表达和富集途径，以及配体-受体（L-R）相互作用。边界样品中T细胞的途径分析显示同种异体移植排斥途径的富集，表明边界样品反映了早期排斥。因此，这允许研究细胞排斥的早期阶段。此外，我们发现，粘着斑（FA），IFNg途径，和内皮粘蛋白（EMCN）显着上调内皮细胞簇（ECs）的边界相比，ECs TCMR。此外，我们发现，周细胞在TCMR似乎有利于内皮细胞通透性相比，边界。类似地，T细胞与临界EC的相互作用与TCMR的不同之处在于涉及DAMPS-TLR相互作用。我们的数据揭示了T细胞，内皮细胞和周细胞在细胞排斥反应中的新作用，为同种异体移植排斥反应的病理生理学提供了新的线索。
Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects. To understand the role of the alloimmune response and the intragraft microenvironment in cellular rejection progression, we conducted a Single nucleus RNA sequencing (snRNA-seq) on one human non-rejecting kidney allograft sample, one borderline sample, and T-cell mediated rejection (TCMR) sample (Banff IIa). We studied the differential gene expression and enriched pathways in different conditions, in addition to ligand-receptor (L-R) interactions. Pathway analysis of T-cells in borderline sample showed enrichment for allograft rejection pathway, suggesting that the borderline sample reflects an early rejection. Hence, this allows for studying the early stages of cellular rejection. Moreover, we showed that focal adhesion (FA), IFNg pathways, and endomucin (EMCN) were significantly upregulated in endothelial cell clusters (ECs) of borderline compared to ECs TCMR. Furthermore, we found that pericytes in TCMR seem to favor endothelial permeability compared to borderline. Similarly, T-cells interaction with ECs in borderline differs from TCMR by involving DAMPS-TLRs interactions. Our data revealed novel roles of T-cells, ECs, and pericytes in cellular rejection progression, providing new clues on the pathophysiology of allograft rejection.
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DOI：
10.1073/pnas.1710964114
发表时间：
2017-11-14
影响因子：
11.1
作者：
Chen, Lihe;Lee, Jae Wook;Knepper, Mark A.
通讯作者：
Knepper, Mark A.
影响因子：
3.3
作者：
Depke, Maren;Breitbach, Katrin;Voelker, Uwe
通讯作者：
Voelker, Uwe
影响因子：
19.6
作者：
Chen, Jianlin;John, Reji;Richardson, James A.;Shelton, John M.;Zhou, Xin J.;Wang, Yanxia;Wu, Qing Qing;Hartono, John R.;Winterberg, Pamela D.;Lu, Christopher Y.
通讯作者：
Lu, Christopher Y.
影响因子：
15.9
作者：
Goldstein, DR;Tesar, BM;Lakkis, FG
通讯作者：
Lakkis, FG
影响因子：
13.6
作者：
Famulski, Konrad S.;de Freitas, Declan G.;Halloran, Philip F.
通讯作者：
Halloran, Philip F.