Alloreactive T Cells Display a Distinct Chemokine Profile in Response to Conditioning in Xenogeneic GVHD Models
Alloreactive T Cells Display a Distinct Chemokine Profile in Response to Conditioning in Xenogeneic GVHD Models
复制标题
同种异体反应性 T 细胞在异种 GVHD 模型中表现出独特的趋化因子特征以适应条件
DOI：
10.1097/tp.0000000000002756
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发表时间：
2019
期刊：
影响因子：
6.2
通讯作者：
Kanda Yoshinobu et al.
中科院分区：
文献类型：
--
作者：
Kawasaki Yasufumi;Sato Kazuya;Kanda Yoshinobu et al.
背景：趋化因子及其受体是预防和治疗移植物抗宿主病（GVHD）的潜在靶点。本研究的目的是确定异种移植模型在宿主和供体趋化因子谱方面的临床相关性，如果是这种情况，方法将5× 10 6人泛T细胞静脉注射入NOD/Shi-scid-1小鼠体内，诱导异种移植物抗宿主病（GVHD），观察C-C趋化因子受体（CCR）5拮抗剂马拉韦罗对GVHD的预防作用。IL 2 r γ null（NOG）小鼠或MHC I/II类缺陷型NOG小鼠在存在或不存在全身照射的情况下在transplantation.Results.中观察到广泛的组织破坏和人T细胞浸润遍及全身，特别是在肺和肝中，但在肠道中相对较轻。与这一发现相一致，定量聚合酶链反应证实了小鼠CXC趋化因子配体（CXCL）9和CXCL 10在肺中的上调，以及CCL 4在肺和肝中的上调，但在肠道中不上调。全身照射的增加（1）导致小鼠CCL 4和CXCL 10的早期释放，（2）上调人T细胞中的许多趋化因子相关基因，（3）诱导人CD 4+和CD 8 + T细胞上的CCR 5和人CD 4 + T细胞上的CXCR 3的更高表达，以及（4）促进它们在器官中的迁移和增殖，导致更严重的组织损伤。在这种情况下，药理学CCR 5封锁既不改善GVHD，也不延长生存在NOG mice.Conclusions。我们的实验数据没有证明CCR 5拮抗剂在清髓性设置GVHD预防的临床效益。
Background.Chemokines and chemokine receptors are potential targets for the prevention and treatment of graft-versus-host disease (GVHD). The objective of the current study is to determine the clinical relevance of xenogeneic transplantation models in terms of host and donor chemokine profiles and, if this is the case, to assess the clinical efficacy of C–C chemokine receptor (CCR) 5 antagonist maraviroc for the prevention of GVHD using this model.Methods.Xenogeneic GVHD was induced by intravenous injection of 5× 10 6 human pan T cells into NOD/Shi-scid-IL2rγ null (NOG) mice or MHC class I/II-deficient NOG mice in the presence or absence of total body irradiation before transplantation.Results.Extensive tissue destruction with human T-cell infiltration was observed throughout the body, particularly in lungs and liver, but relatively mild in gut. Consistent with this finding, quantitative polymerase chain reaction confirmed the upregulation of mouse CXC chemokine ligand (CXCL) 9 and CXCL10 in lungs and CCL4 in lungs and liver but not in gut. The addition of total body irradiation (1) led to the early release of mouse CCL4 and CXCL10,(2) upregulated a number of chemokine-related genes in human T cells,(3) induced higher expression of CCR5 on human CD4+ and CD8+ T cells and CXCR3 on human CD4+ T cells, and (4) promoted their migration and proliferation in organs, resulting in more severe tissue damage. In this context, pharmacological CCR5 blockade neither ameliorated GVHD nor prolonged survival in NOG mice.Conclusions.Our experimental data do not demonstrate clinical benefit of CCR5 antagonist for the prevention of GVHD in a myeloablative setting.