Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection.
Bone marrow transplant-induced alterations in Notch signaling promote pathologic Th17 responses to γ-herpesvirus infection.
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DOI：
10.1038/mi.2017.85
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发表时间：
2018-05
影响因子：
8
通讯作者：
Moore BB
中科院分区：
文献类型：
--
作者：
Gurczynski SJ;Zhou X;Flaherty M;Wilke CA;Moore BB
特发性肺炎综合征（IPS）是造血干细胞移植（HSCT）后常见的、往往致命的并发症，其特征是严重的肺炎和间质纤维化。感染鼠γ疱疹病毒（γHV-68）的完全重建的同基因骨髓移植（BMT）小鼠发生IL-17驱动的肺炎和纤维化，与IPS的临床表现相似。我们发现CD 103+和CD 11b+树突状细胞（DCs）选择性缺乏Notch配体DLL 4，BMT和CD 4 + T细胞分离自感染BMT小鼠的肺和脾显示Notch信号转导缺陷。移植了CD 4-Cre驱动的显性阴性Notch转录调节因子Mastermind样（CCD小鼠）骨髓的小鼠在肺中显示出升高的IL-17和TGFβ，Th 17细胞进一步扩增，并且比WT-BMT小鼠发生更多的纤维化。用重组Notch配体DLL 4培养BMT肺白细胞恢复了Notch信号传导并降低了IL-17的产生。CD 11 c + DC的连续转移可以恢复WT-BMT小鼠的Th 1和限制Th 17，但不能恢复CCD-BMT小鼠的Th 1和限制Th 17，这表明在同基因BMT小鼠中重建后，特异性DC /CD 4 + T细胞Notch相互作用调节IL-17的产生。鉴于最近的临床观察表明，移植后肺部并发症的患者隐匿性疱疹病毒感染，这些数据提供了机制的见解，并建议这些破坏性的条件下的潜在疗法。
Idiopathic pneumonia syndrome (IPS) is a common, often fatal, complication following hematopoietic stem cell transplantation (HSCT) characterized by severe pneumonitis and interstitial fibrosis. Fully reconstituted syngeneic bone marrow transplant (BMT) mice infected with murine gammaherpesvirus (γHV-68) develop IL-17-driven pneumonitis and fibrosis which mimics clinical manifestations of IPS. We found CD103+ and CD11b+ dendritic cells (DCs) are selectively deficient for the Notch ligand, DLL4, following BMT and CD4+ T-cells isolated from lungs and spleens of infected BMT mice display Notch signaling defects. Mice transplanted with CD4-Cre-driven dominant-negative Notch transcriptional regulator Mastermind Like (CCD mice) bone marrow displayed elevated IL-17 and TGFβ in the lungs, a further expansion of Th17 cells, and developed more fibrosis than WT-BMT mice. Culture of BMT lung leukocytes with recombinant Notch ligand, DLL4, restored Notch signaling and decreased production of IL-17. Adoptive transfer of CD11c+ DCs could restore Th1 and limit Th17 in WT-BMT but not CCD-BMT mice indicating a specific DC / CD4+ T-cell Notch interaction modulates IL-17 production following reconstitution in syngeneic BMT mice. Given recent clinical observations showing that patients with pulmonary complications post-transplant harbor occult herpesvirus infections, these data provide mechanistic insight and suggest potential therapies for these devastating conditions.
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DOI：
10.4049/jimmunol.1003658
发表时间：
2011-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Keerthivasan S;Suleiman R;Lawlor R;Roderick J;Bates T;Minter L;Anguita J;Juncadella I;Nickoloff BJ;Le Poole IC;Miele L;Osborne BA
通讯作者：
Osborne BA
影响因子：
3.7
作者：
Huang, Huei-Mei;Hsiao, George;Lee, Yueh-Lun
通讯作者：
Lee, Yueh-Lun
DOI：
10.1016/j.bbrc.2011.03.042
发表时间：
2011-04-15
影响因子：
3.1
作者：
Han, Jianxun;Allalunis-Turner, Joan;Hendzel, Michael J.
通讯作者：
Hendzel, Michael J.
影响因子：
4.6
作者：
Coutaz M;Hurrell BP;Auderset F;Wang H;Siegert S;Eberl G;Ho PC;Radtke F;Tacchini-Cottier F
通讯作者：
Tacchini-Cottier F
Notch配体DLL4定义了人类树突状细胞调节Th1和Th17分化的能力
DOI：
10.4049/jimmunol.1501310
发表时间：
2016-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Meng L;Bai Z;He S;Mochizuki K;Liu Y;Purushe J;Sun H;Wang J;Yagita H;Mineishi S;Fung H;Yanik GA;Caricchio R;Fan X;Crisalli LM;Hexner EO;Reshef R;Zhang Y;Zhang Y
通讯作者：
Zhang Y