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
Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania (Penn), Philadelphia, Pennsylvania, USA.
Center for Cellular Immunotherapies and.
JCI Insight. 2025 Apr 15;10(10). doi: 10.1172/jci.insight.176596. eCollection 2025 May 22.
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.
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。
Biol Blood Marrow Transplant. 2012-3-24
Front Immunol. 2024-12-17
Neurol Neuroimmunol Neuroinflamm. 2024-1
Am J Respir Crit Care Med. 2023-12-1
Nat Commun. 2023-7-29