Australian Cancer Research Foundation (ACRF) Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia.
Department of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
Front Immunol. 2023 Sep 25;14:1213560. doi: 10.3389/fimmu.2023.1213560. eCollection 2023.
Poor graft function (PGF), manifested by multilineage cytopenias and complete donor chimerism post-allogeneic stem cell transplantation (alloSCT), and acquired aplastic anaemia (AA) are immune-mediated acquired bone marrow (BM) failure syndromes with a similar clinical presentation. In this study, we used spatial proteomics to compare the immunobiology of the BM microenvironment and identify common mechanisms of immune dysregulation under these conditions. Archival BM trephines from patients exhibited downregulation of the immunoregulatory protein VISTA and the M2 macrophage marker and suppressor of T-cell activation ARG1 with increased expression of the immune checkpoint B7-H3 compared to normal controls. Increased CD163 and CD14 expression suggested monocyte/macrophage skewing, which, combined with dysregulation of STING and VISTA, is indicative of an environment of reduced immunoregulation resulting in the profound suppression of hematopoiesis in these two conditions. There were no changes in the immune microenvironment between paired diagnostic AA and secondary MDS/AML samples suggesting that leukaemic clones develop in the impaired immune microenvironment of AA without the need for further alterations. Of the eight proteins with dysregulated expression shared by diagnostic AA and PGF, the diagnostic AA samples had a greater fold change in expression than PGF, suggesting that these diseases represent a spectrum of immune dysregulation. Unexpectedly, analysis of samples from patients with good graft function post-alloSCT demonstrated significant changes in the immune microenvironment compared to normal controls, with downregulation of CD44, STING, VISTA, and ARG1, suggesting that recovery of multilineage haematopoiesis post-alloSCT does not reflect recovery of immune function and may prime patients for the development of PGF upon further inflammatory insult. The demonstrable similarities in the immunopathology of AA and PGF will allow the design of clinical interventions that include both patient cohorts to accelerate therapeutic discovery and translation.
不良移植物功能（PGF）表现为多谱系细胞减少症和异基因干细胞移植（alloSCT）后完全供体嵌合，以及获得性再生障碍性贫血（AA），是具有相似临床表现的免疫介导的获得性骨髓（BM）衰竭综合征。在这项研究中，我们使用空间蛋白质组学来比较 BM 微环境的免疫生物学，并确定在这些情况下免疫失调的共同机制。与正常对照相比，来自患者的存档 BM 活检标本显示免疫调节蛋白 VISTA 和 M2 巨噬细胞标志物以及 T 细胞激活抑制剂 ARG1 的下调，而免疫检查点 B7-H3 的表达增加。增加的 CD163 和 CD14 表达表明单核细胞/巨噬细胞偏斜，与 STING 和 VISTA 的失调相结合，表明免疫调节减少的环境导致这两种情况中造血的严重抑制。配对的诊断性 AA 和继发性 MDS/AML 样本之间的免疫微环境没有变化，这表明白血病克隆在 AA 的受损免疫微环境中发展，而无需进一步改变。在诊断性 AA 和 PGF 共有的 8 个表达失调的蛋白质中，诊断性 AA 样本的表达变化幅度大于 PGF，这表明这些疾病代表了免疫失调的一个谱。出乎意料的是，与正常对照相比，alloSCT 后移植物功能良好的患者样本的免疫微环境发生了显著变化，CD44、STING、VISTA 和 ARG1 下调，这表明 alloSCT 后多谱系造血的恢复并不反映免疫功能的恢复，并且可能使患者在受到进一步炎症损伤时易发生 PGF。AA 和 PGF 的免疫病理学的明显相似性将允许设计包括两个患者群体的临床干预措施，以加速治疗发现和转化。
