Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice.
Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice.
复制标题
DOI：
10.3389/fimmu.2018.01943
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Baron F
中科院分区：
文献类型：
--
作者：
Ehx G;Somja J;Warnatz HJ;Ritacco C;Hannon M;Delens L;Fransolet G;Delvenne P;Muller J;Beguin Y;Lehrach H;Belle L;Humblet-Baron S;Baron F
尽管越来越多地使用人源化小鼠模型来研究预防移植物抗宿主病（GVHD）的新方法，但在这些模型中异种GVHD（xGVHD）的发病机制仍然被误解。本研究的目的是描述输注人PBMC的NOD/LtSz-PrkdcscidIL 2 r γ tm 1 Wjl（NSG）小鼠的发病机制，并通过利用下一代技术评估NSG小鼠细胞（NSG-HLA-A2/HHD小鼠）表达HLA-A0201对xGVHD和移植物抗白血病（GvL）效应的影响。我们发现，移植后从NSG小鼠中回收的T细胞上调了参与细胞增殖的基因表达，以及TCR、共刺激、IL-2/STAT 5、mTOR和Aurora激酶A通路。T细胞主要具有效应记忆或效应表型，并表现出Th 1/Tc 1偏态分化。与输注时相比，脾和肺（xGVHD靶器官）中的TCRβ库多样性显著降低。在基线和移植小鼠中特定克隆型的频率之间没有相关性。最后，通过NSG小鼠表达HLA-A0201导致更严重的xGVHD和增强的GvL对HLA-A2+白血病细胞的作用。总之，我们的数据表明，xGVHD的发病机制与人类GVHD的重要特征，NSG-HLA-A2/HHD小鼠可以作为更好的模型来研究GVHD和GvL效应。
Despite the increasing use of humanized mouse models to study new approaches of graft-versus-host disease (GVHD) prevention, the pathogenesis of xenogeneic GVHD (xGVHD) in these models remains misunderstood. The aim of this study is to describe this pathogenesis in NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice infused with human PBMCs and to assess the impact of the expression of HLA-A0201 by NSG mice cells (NSG-HLA-A2/HHD mice) on xGVHD and graft-versus-leukemia (GvL) effects, by taking advantage of next-generation technologies. We found that T cells recovered from NSG mice after transplantation had upregulated expression of genes involved in cell proliferation, as well as in TCR, co-stimulatory, IL-2/STAT5, mTOR and Aurora kinase A pathways. T cells had mainly an effector memory or an effector phenotype and exhibited a Th1/Tc1-skewed differentiation. TCRβ repertoire diversity was markedly lower both in the spleen and lungs (a xGVHD target organ) than at infusion. There was no correlation between the frequencies of specific clonotypes at baseline and in transplanted mice. Finally, expression of HLA-A0201 by NSG mice led to more severe xGVHD and enhanced GvL effects toward HLA-A2+ leukemic cells. Altogether our data demonstrate that the pathogenesis of xGVHD shares important features with human GVHD and that NSG-HLA-A2/HHD mice could serve as better model to study GVHD and GvL effects.
登录
查看更多内容
DOI：
10.1084/jem.178.6.2185
发表时间：
1993-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Freeman GJ;Borriello F;Hodes RJ;Reiser H;Gribben JG;Ng JW;Kim J;Goldberg JM;Hathcock K;Laszlo G
通讯作者：
Laszlo G
影响因子：
7.3
作者：
Ghimire S;Weber D;Mavin E;Wang XN;Dickinson AM;Holler E
通讯作者：
Holler E
影响因子：
17.1
作者：
Cuende, Julia;Lienart, Stephanie;Lucas, Sophie
通讯作者：
Lucas, Sophie
影响因子：
2.9
作者：
Hannon, Muriel;Lechanteur, Chantal;Baron, Frederic
通讯作者：
Baron, Frederic
影响因子：
20.3
作者：
Blazar, BR;Taylor, PA;Vallera, DA
通讯作者：
Vallera, DA