Arsenic Trioxide Prevents Murine Sclerodermatous Graft-versus-Host Disease
Arsenic Trioxide Prevents Murine Sclerodermatous Graft-versus-Host Disease
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DOI：
10.4049/jimmunol.1103538
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发表时间：
2012-05-15
影响因子：
4.4
通讯作者：
Batteux, Frederic
中科院分区：
文献类型：
--
作者：
Kavian, Niloufar;Marut, Wioleta;Batteux, Frederic
异基因造血干细胞移植后发生慢性移植物抗宿主病（GVHD）。它是由活化的APC（如浆细胞样树突状细胞（pDC））触发的轻微MHC不相容性诱导的同种异体反应过程引起的，并导致CD 4 T细胞的活化。因此，我们测试了是否CD 4（+）和pDCs，产生高水平活性氧的活化细胞，可以被三氧化二砷（As 2 O3）杀死，三氧化二砷是一种用于治疗急性早幼粒细胞白血病的化疗药物。事实上，As 2 O3通过诱导超过致死阈值的强大氧化应激来发挥其细胞毒性作用。采用BALB/c小鼠经全身照射诱导硬皮病GVHD，然后进行B10.D2骨髓和脾细胞移植。同时每天腹腔注射As 2 O3处理小鼠。移植小鼠表现出严重的临床症状，包括腹泻、脱发、血管炎以及皮肤和内脏器官的纤维化。在用As 2 O3处理的小鼠中，症状显著消除。这些有益的作用是通过谷胱甘肽的消耗和过氧化氢的过量产生介导的，过氧化氢杀死活化的CD 4（+）T细胞和pDC。在硬皮病GVHD模型中，As 2 O3提供了显著的改善，该模型将纤维化与免疫激活相关联，这为评估As 2 O3在慢性GVHD患者管理中的作用提供了依据。免疫学杂志，2012，188：5142-5149。
Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor MHC incompatibilities triggered by activated APCs, such as plasmacytoid dendritic cells (pDCs), and leading to the activation of CD4 T cells. Therefore, we tested whether CD4(+) and pDCs, activated cells that produce high levels of reactive oxygen species, could be killed by arsenic trioxide (As2O3), a chemotherapeutic drug used in the treatment of acute promyelocytic leukemia. Indeed, As2O3 exerts its cytotoxic effects by inducing a powerful oxidative stress that exceeds the lethal threshold. Sclerodermatous GVHD was induced in BALB/c mice by body irradiation, followed by B10.D2 bone marrow and spleen cell transplantation. Mice were simultaneously treated with daily i.p. injections of As2O3. Transplanted mice displayed severe clinical symptoms, including diarrhea, alopecia, vasculitis, and fibrosis of the skin and visceral organs. The symptoms were dramatically abrogated in mice treated with As2O3. These beneficial effects were mediated through the depletion of glutathione and the overproduction of H2O2 that killed activated CD4(+) T cells and pDCs. The dramatic improvement provided by As2O3 in the model of sclerodermatous GVHD that associates fibrosis with immune activation provides a rationale for the evaluation of As2O3 in the management of patients affected by chronic GVHD. The Journal of Immunology, 2012, 188: 5142-5149.