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免疫细胞和基质细胞在人类闭塞性细支气管炎综合征发病机制中的共同作用。

Shared roles of immune and stromal cells in the pathogenesis of human bronchiolitis obliterans syndrome.

作者信息

Mellors Patrick W, Lange Ana N, Casino Remondo Bruno, Shestov Maksim, Planer Joseph D, Peterson Andrew R, Ying Yun, Zhou Su, Christie Jason D, Diamond Joshua M, Cantu Edward, Basil Maria C, Gill Saar

机构信息

Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania (Penn), Philadelphia, Pennsylvania, USA.

Center for Cellular Immunotherapies and.

出版信息

JCI Insight. 2025 Apr 15;10(10). doi: 10.1172/jci.insight.176596. eCollection 2025 May 22.


DOI:10.1172/jci.insight.176596
PMID:40232854
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12128974/
Abstract

Bronchiolitis obliterans syndrome (BOS) is a progressive, fatal obstructive lung disease that occurs following lung transplant, where it is termed chronic lung allograft dysfunction BOS (CLAD-BOS), or as the primary manifestation of pulmonary chronic graft versus host disease (cGVHD-BOS) following allogeneic hematopoietic stem cell transplant. Disease pathogenesis is poorly understood; however, chronic alloreactivity is common to both conditions, suggesting a shared pathophysiology. We performed single-cell RNA-Seq (scRNA-Seq) on explanted human lungs from 4 patients with CLAD-BOS, 3 patients with cGVHD-BOS, and 3 deceased controls to identify cell types, genes, and pathways enriched in BOS to better understand disease mechanisms. In both forms of BOS, we found an expanded population of CD8+ tissue resident memory T cells (TRM), which was distinct to BOS compared with other chronic lung diseases. In addition, BOS samples expressed genes and pathways associated with macrophage chemotaxis and proliferation, including in nonimmune cell populations. We also identified dysfunctional stromal cells in BOS, characterized by pro- and antifibrotic gene programs. These data suggest substantial cellular and molecular overlap between CLAD- and cGVHD-BOS and, therefore, common pathways for possible therapeutic intervention.

摘要

闭塞性细支气管炎综合征(BOS)是一种进行性、致命的阻塞性肺病,发生于肺移植后,被称为慢性肺移植功能障碍BOS(CLAD - BOS),或作为异基因造血干细胞移植后肺慢性移植物抗宿主病(cGVHD - BOS)的主要表现。疾病发病机制尚不清楚;然而,慢性同种异体反应在这两种情况下都很常见,提示存在共同的病理生理学机制。我们对4例CLAD - BOS患者、3例cGVHD - BOS患者和3例死亡对照的离体人肺进行了单细胞RNA测序(scRNA - Seq),以确定BOS中富集的细胞类型、基因和通路,从而更好地理解疾病机制。在两种形式的BOS中,我们发现CD8 + 组织驻留记忆T细胞(TRM)群体扩大,与其他慢性肺病相比,这是BOS所特有的。此外,BOS样本表达了与巨噬细胞趋化和增殖相关的基因和通路,包括在非免疫细胞群体中。我们还在BOS中鉴定出功能失调的基质细胞,其特征是具有促纤维化和抗纤维化基因程序。这些数据表明CLAD - BOS和cGVHD - BOS之间存在大量细胞和分子重叠,因此可能存在共同的治疗干预途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/f0d1b29c7e5e/jciinsight-10-176596-g243.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/f9506265f49f/jciinsight-10-176596-g237.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/1119f5af8e71/jciinsight-10-176596-g238.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/9e8a7fbeffeb/jciinsight-10-176596-g239.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/03afe88ba4f2/jciinsight-10-176596-g240.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/b4d23a35f754/jciinsight-10-176596-g241.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/a9ee352ecc75/jciinsight-10-176596-g242.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/f0d1b29c7e5e/jciinsight-10-176596-g243.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/f9506265f49f/jciinsight-10-176596-g237.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/1119f5af8e71/jciinsight-10-176596-g238.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/9e8a7fbeffeb/jciinsight-10-176596-g239.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/03afe88ba4f2/jciinsight-10-176596-g240.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/b4d23a35f754/jciinsight-10-176596-g241.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/a9ee352ecc75/jciinsight-10-176596-g242.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5121/12128974/f0d1b29c7e5e/jciinsight-10-176596-g243.jpg

相似文献

[1]
Shared roles of immune and stromal cells in the pathogenesis of human bronchiolitis obliterans syndrome.

JCI Insight. 2025-4-15

[2]
Clonal GZMKCD8 T cells are identified as a hallmark of the pathogenesis of cGVHD-induced bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation.

EBioMedicine. 2025-2

[3]
A review of the therapeutic potential of the cysteinyl leukotriene antagonist Montelukast in the treatment of bronchiolitis obliterans syndrome following lung and hematopoietic-stem cell transplantation and its possible mechanisms.

Ther Adv Respir Dis. 2024

[4]
Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease.

Biol Blood Marrow Transplant. 2009-11-5

[5]
Time to explore preventive and novel therapies for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation.

Biol Blood Marrow Transplant. 2012-3-24

[6]
Immune dysregulation as a driver of bronchiolitis obliterans.

Front Immunol. 2024-12-17

[7]
Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Am J Hematol. 2014-2-21

[8]
The Lymphatic Phenotype of Lung Allografts in Patients With Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome.

Transplantation. 2017-2

[9]
Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation.

Am J Transplant. 2016-8

[10]
Self-reactive antibodies associated with bronchiolitis obliterans syndrome subtype of chronic lung allograft dysfunction.

Hum Immunol. 2021-1

本文引用的文献

[1]
Resident Memory-like CD8 T Cells Are Involved in Chronic Inflammatory and Neurodegenerative Diseases in the CNS.

Neurol Neuroimmunol Neuroinflamm. 2024-1

[2]
Activation of CD8 T Cells in Chronic Obstructive Pulmonary Disease Lung.

Am J Respir Crit Care Med. 2023-12-1

[3]
Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death.

J Clin Invest. 2023-8-1

[4]
Guided construction of single cell reference for human and mouse lung.

Nat Commun. 2023-7-29

[5]
Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors.

Cell Rep Med. 2023-6-20

[6]
JAK-STAT activation contributes to cytotoxic T cell-mediated basal cell death in human chronic lung allograft dysfunction.

JCI Insight. 2023-3-22

[7]
Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer.

Br J Cancer. 2023-5

[8]
Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.

Immunity. 2023-3-14

[9]
Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.

Nat Commun. 2023-2-2

[10]
Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade.

Cancer Immunol Res. 2023-4-3

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