在小鼠体内T细胞表达嵌合抗原受体绑定乙肝病毒包膜蛋白控

StephenW

T Cells Expressing a Chimeric Antigen Receptor That Binds Hepatitis B Virus Envelope Proteins Control Virus Replication in Mice

    Karin Krebs
    ,
    Nina Böttinger
    ,
    Li–Rung Huang
    ,
    Markus Chmielewski
    ,
    Silke Arzberger
    ,
    Georg Gasteiger
    ,
    Clemens Jäger
    ,
    Edgar Schmitt
    ,
    Felix Bohne
    ,
    Michaela Aichler
    ,
    Wolfgang Uckert
    ,
    Hinrich Abken
    ,
    Mathias Heikenwalder
    ,
    Percy Knolle
    ,
    Ulrike Protzeremail address

Received 19 August 2012; accepted 17 April 2013. published online 01 May 2013.

  

Background & Aims

Antiviral agents suppress hepatitis B virus (HBV) replication but do not clear the infection. A strong effector T-cell response is required to eradicate HBV, but this does not occur in patients with chronic infection. T cells might be directed toward virus-infected cells by expressing HBV-specific receptors and thereby clear HBV and help to prevent development of liver cancer. In mice, we studied whether redirected T cells can engraft after adoptive transfer, without prior T-cell depletion, and whether the large amounts of circulating viral antigens inactivate the transferred T cells or lead to uncontrolled immune-mediated damage.
Methods

CD8+ T cells were isolated from mice and stimulated using an optimized protocol. Chimeric antigen receptors (CARs) that bind HBV envelope proteins (S-CAR) and activate T cells were expressed on the surface of cells using retroviral vectors. S-CAR–expressing CD8+ T cells, which carried the marker CD45.1, were injected into CD45.2+ HBV transgenic mice. We compared these mice with mice that received CD8+ T cells induced by vaccination, cells that express a CAR without a proper signaling domain, or cells that express a CAR that does not bind HBV proteins (controls).
Results

CD8+ T cells that expressed HBV-specific CARs recognized different HBV subtypes and were able to engraft and expand in immune-competent HBV transgenic mice. After adoptive transfer, the S-CAR–expressing T cells localized to and functioned in the liver and rapidly and efficiently controlled HBV replication compared with controls, causing only transient liver damage. The large amount of circulating viral antigen did not impair or overactivate the S-CAR–grafted T cells.
Conclusions

T cells with a CAR specific for HBV envelope proteins localize to the liver in mice to reduce HBV replication, causing only transient liver damage. This immune cell therapy might be developed for patients with chronic hepatitis B, regardless of their HLA type.

StephenW

背景与目的

抗病毒药物抑制B型肝炎病毒（HBV）复制，但不清除感染。需要一个强大的效应T细胞反应，以消除乙肝病毒，但这种情况不会发生在慢性感染患者。 T细胞可能会指向病毒感染的细胞表达HBV特异性受体，从而清除HBV和帮助，以防止发展为肝癌。在小鼠实验中，我们研究了重定向的T细胞是否可以嫁接过继转移，恕不另行T细胞耗竭，以及是否大量的循环病毒抗原灭活T细胞转移或导致失控的免疫介导损伤。
方法

小鼠中分离出CD8 + T细胞，刺激使用一个优化的协议。嵌合抗原受体（中亚）结合HBV的包膜蛋白（S-CAR），激活T细胞，使用逆转录病毒载体的细胞的表面上表达。 S-CAR表达的CD8 + T细胞，进行标记CD45.1 CD45.2 + HBV转基因小鼠，分别注入。我们比较这些老鼠与老鼠接受诱导CD8 + T细胞通过接种疫苗，细胞表达一辆车，没有一个适当的信令域，或一辆汽车，不具约束力的HBV蛋白（对照组）的细胞表达。
结果

CD8 + T细胞表达HBV特异性汽车认识不同的HBV亚型和得以嫁接和扩大免疫能力的HBV转基因小鼠。 S-CAR表达的T细胞过继转移后，本地化和作用在肝脏中，迅速，有效地控制HBV复制与对照组相比，造成唯一的一过性肝损伤。循环病毒抗原的大量不损害或S-CAR接枝的T细胞overactivate。
结论

HBV包膜蛋白的T细胞与CAR的具体定位在小鼠肝脏减少HBV的复制，导致唯一的一过性肝损伤。这种免疫细胞疗法可能会发展为慢性乙肝患者，无论他们的HLA类型。

MP4

http://www.hbvhbv.info/forum/for ... fromuid-320872.html
你发过了

StephenW

回复 MP4 的帖子

谢谢。你是对的.
许多文章发布两次，第一个网上，然后在打印.

咬牙硬挺

发过也感谢分享