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小鼠同种异基因CD19 CAR-T细胞抗白血病的能力及其导致致命GVHD的潜力

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发表于 2016-1-9 11:53:53 | 显示全部楼层 |阅读模式
Murine allogeneic CD19 CAR T-cells harbor potent anti-leukemic activity but have the potential to mediate lethal GVHD
Acute lymphoblastic leukemia (ALL) persisting or relapsing following a bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric-antigen-receptor (CAR) T-cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T-cells, that may be more functional than T-cells derived from patients with leukemia but have the potential to mediate graft versus host disease (GVHD). We and others have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T-cells. Allogeneic donor-derived CD19-CAR T-cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T-cells mediated lethal acute GVHD with early mortality,atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T-cells show initial expansion as effector T-cells, with a higher peak but rapid deletion of allogeneic CAR T-cells.
Interestingly, CAR mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions inducing GVHD. Indeed, serum interleukin-6 (IL-6) was elevated only in the presence of both leukemia and CAR T-cells, and IL-6 neutralization ameliorated severity of GVHD in a delayed-DLI model. Finally, allogeneic CD4+ CAR T-cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that allogeneic CAR T-cells have the capacity to drive GVHD, with significant expansion and later deletion.
小鼠同种异基因CD19 CAR-T细胞抗白血病的能力及其导致致命GVHD的潜力
急性淋巴细胞白血病(ALL在进行骨髓移植(BMT后有一个令人沮丧的复发或者持续性发作。嵌合抗原受体(CART细胞使用为这种疾病的治疗提供了一个机会,效果比使用白血病患者供体来源的T细胞更好,然而这可能会出现更多的移植物抗宿主病(GVHD)的潜力。我们和其他人以前就发现,在异基因的环境中,肿瘤特异性T细胞会出现功能障碍。在这里,我们研究骨髓移植之后CAR-T细胞的功能,使用一个免疫小鼠模型,在进行异基因移植之后注射供者来源的CD-19 CAR-T细胞。异基因来源的CD19 CAR-T细胞消除残余的ALL的能力等同于那些使用同基因骨髓移植的管理组。奇怪的是,异基因CAR-T细胞介导的致命急性的GVHD伴有早期的死亡率,非典型的轻微不匹配模型。我们发现,异体或者同系的CAR-T细胞在早期均有一个快速扩增的阶段,会有一个很高的峰值,然而异体的CAR-T细胞会迅速消减。有趣的是,CAR介导的急性GVHD只有在白血病的治疗中存在,这说明了CAR靶向作用导致了GVHD的发生。事实上,血清白细胞介素-6IL-6)只在T细胞白血病和CAR存在时升高,IL-6中和改善延迟了模型的GVHD的发生。最后,异体CD4+ T细胞是导致CAR引起GVHD的原因,这与他们产生IL-6CAR刺激能力相关。总之,我们表明,同种异体T细胞对移植物抗宿主病有驱动能力,具有显著的扩张和后来的缺失。
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