Département 3I Infection, Immunité et Inflammation , Institut Cochin, INSERM U1016, Université de Paris, Paris, France.
MEDSENIC SAS, Strasbourg, France.
Front Immunol. 2022 Aug 9;13:917739. doi: 10.3389/fimmu.2022.917739. eCollection 2022.
Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. , among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4 T lymphocytes during a mixed lymphocyte reaction (MLR). , in a cGvHD mouse model, daily injections of ATO 2.5 µg/g + CuCl 0.5 µg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 µg/g. Our results show that the addition of CuCl improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress.
移植物抗宿主病（GvHD）是造血干细胞移植的主要并发症。GvHD 的特征是免疫细胞的慢性激活，导致全身炎症、自身免疫、纤维化，最终导致死亡。三氧化二砷（ATO）是一种临床试验中的治疗药物，用于治疗系统性红斑狼疮（SLE）和慢性移植物抗宿主病（cGvHD）患者。尽管会发生不良反应，并且可能需要中断治疗，但这种治疗方法确实相当安全。本研究的目的是将 ATO 与二价阳离子结合，在小鼠模型中通过 ATO 的活性氧（ROS）介导的作用产生 Fenton 或类 Fenton 反应，从而增强对活化免疫细胞的删除，从而使较低和更安全的 ATO 浓度能够用于治疗 cGvHD 患者。, 在测试的各种二价阳离子组合中，我们观察到 ATO 和 CuCl（氯化铜）的组合在 HL-60 和 A20 细胞中诱导高水平的氧化应激。此外，这种联合治疗还降低了混合淋巴细胞反应（MLR）中 CD4 T 淋巴细胞的增殖。, 在 cGvHD 小鼠模型中，每日注射 ATO 2.5 µg/g + CuCl 0.5 µg/g 可降低淋巴细胞激活和纤维化，其效果与 ATO 5 µg/g 相当。我们的结果表明，CuCl 的加入改善了 ATO 的效果，并显著限制了疾病的发展。这种联合治疗可能对人类患者有实际益处，可大大降低已知的 ATO 副作用，并优化对氧化应激敏感的活化细胞为特征的病理的 ATO 治疗。
