Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Br J Dermatol. 2024 Feb 16;190(3):402-414. doi: 10.1093/bjd/ljad402.
Graft-versus-host disease (GvHD) is a major life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT), limiting the broad application of HSCT for haematological malignancies. Cutaneous GvHD is described as a post-transplant inflammatory reaction by skin-infiltrating donor T cells and remaining recipient tissue-resident memory T cells. Despite the major influence of lymphocytes on GvHD pathogenesis, the complex role of mononuclear phagocytes (MNPs) in tissues affected by GvHD is increasingly appreciated.
To characterize the identity, origin and functions of MNPs in patients with acute cutaneous GvHD.
Using single-cell RNA sequencing and multiplex tissue immunofluorescence, we identified an increased abundance of MNPs in skin and blood from 36 patients with acute cutaneous GvHD. In cases of sex-mismatched transplantation, we used expression of X-linked genes to detect rapid tissue adaptation of newly recruited donor MNPs resulting in similar transcriptional states of host- and donor-derived macrophages within GvHD skin lesions.
We showed that cutaneous GvHD lesions harbour expanded CD163+ tissue-resident macrophage populations with anti-inflammatory and tissue-remodelling properties including interleukin-10 cytokine production. Cell-cell interaction analyses revealed putative signalling to strengthen regulatory T-cell responses. Notably, macrophage polarization in chronic cutaneous GvHD types was proinflammatory and drastically differed from acute GvHD, supporting the notion of distinct cellular players in different clinical GvHD subtypes.
Overall, our data reveal a surprisingly dynamic role of MNPs after HSCT. Specific and time-resolved targeting to repolarize this cell subset may present a promising therapeutic strategy in combatting GvHD skin inflammation.
移植物抗宿主病（GvHD）是异基因造血干细胞移植（HSCT）的一种主要危及生命的并发症，限制了 HSCT 在血液恶性肿瘤中的广泛应用。皮肤 GvHD 被描述为浸润皮肤的供体 T 细胞和残留的受者组织驻留记忆 T 细胞的移植后炎症反应。尽管淋巴细胞对 GvHD 发病机制有重大影响，但单核吞噬细胞（MNPs）在受 GvHD 影响的组织中的复杂作用正日益受到重视。
描述急性皮肤 GvHD 患者中 MNPs 的特征、来源和功能。
我们使用单细胞 RNA 测序和多重组织免疫荧光，在 36 例急性皮肤 GvHD 患者的皮肤和血液中鉴定到 MNPs 的丰度增加。在性别错配移植的情况下，我们使用 X 连锁基因的表达来检测新募集的供体 MNPs 在组织中的快速适应，导致 GvHD 皮肤病变中宿主和供体来源的巨噬细胞具有相似的转录状态。
我们表明，皮肤 GvHD 病变中存在扩增的 CD163+组织驻留巨噬细胞群体，具有抗炎和组织重塑特性，包括白细胞介素 10 细胞因子的产生。细胞间相互作用分析显示，存在潜在的信号来增强调节性 T 细胞的反应。值得注意的是，慢性皮肤 GvHD 类型中的巨噬细胞极化呈促炎状态，与急性 GvHD 明显不同，这支持了不同临床 GvHD 亚型中存在不同细胞成分的观点。
总的来说，我们的数据揭示了 HSCT 后 MNPs 的惊人动态作用。针对该细胞亚群的特异性和时间分辨靶向重极化可能是对抗 GvHD 皮肤炎症的一种有前途的治疗策略。
