断点群集区域
免疫学
布鲁顿酪氨酸激酶
淋巴增殖性疾病
伊布替尼
生物
离体
B细胞
癌症研究
爱泼斯坦-巴尔病毒
体内
B细胞受体
疾病
病毒
医学
受体
白血病
抗体
慢性淋巴细胞白血病
病理
遗传学
酪氨酸激酶
作者
Ting-ting Zhang,Rene Yu-Hong Cheng,Andee R. Ott,Noelle P. Dahl,Emmaline R. Suchland,Claire M. Stoffers,G. W. Asher,Deyin Hou,Christopher D. Thouvenel,Thomas J. Hill,Karen Sommer,Richard G. James
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2024-04-10
卷期号:16 (742)
标识
DOI:10.1126/scitranslmed.adh8846
摘要
Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo-differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV+ peripheral blood-derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV+ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD.
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