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过继性T细胞转移的临床反应可以用自体免疫的人源化小鼠模型来模拟

作者:Inge Marie Svane, Lisa M. Nilsson & Jonas A. Nilss

自体肿瘤浸润T细胞的免疫抑制点抑制剂和过继性细胞转移(ACT)在黑色素瘤患者中表现出持久的反应。为了研究人的ACT和免疫疗法,我们已经开发了pdxv2.0 -黑色素瘤PDX模型, 来自同一病人的肿瘤细胞和肿瘤浸润T细胞,按顺序移植入非肥胖糖尿病/重症联合免疫缺陷/γ链基因敲除小鼠(NOG / NSG)。在该模型中,T细胞存活/发生效用的关键在于白细胞介素-2(IL-2)的持续存在。如果自体肿瘤细胞和T细胞来自临床对ACT有客观反应的患者,生长在pdxv2.0中的肿瘤会被根除。但是,T细胞如果来自对ACT没反应的患者,就不能杀死pdxv2.0中的肿瘤细胞

总之,pdxv2.0提供潜在的框架,进一步模型化遗传多样性人类癌症,以评估免疫疗法以及联合治疗的疗效。

Effective in vitro cytotoxicity does not result in effective anti-tumoral activity in NOG mice. a Schematic representation of the humanization process (PDXv2.0). b Melanoma cells from patient #33 (MM33) were transduced with a luciferase lentivirus. Cells were plated in a 96-well plate and were mixed with post-REP TILs from the original tumor. Luciferin was added to the media and the viability of the luciferase-expressing tumor cells was measured in a luminometer. The experiment was done in triplicates and the error bar represents ± SEM. c MM33 cells were transplanted into ten NOG mice. 1 week after transplantation, mice were randomized into two groups, one of which received a tail vein injection with autologous TILs. 45,000 U IL-2 was given daily for 3 days following TIL injection and thereafter twice weekly during 3 weeks. Tumor growth was measured using calipers. P-values are from a multiple t-test analysis. d, e When robust progression was noted in all mice, the mice with the slowest and fastest growing tumors in each group were sacrificed and the tumors were analyzed by immunohistochemistry (d, bar = 50 µm) or flow cytometry e for indicated markers. When PD1 expression was observed, anti-PD1 antibody pembroluzimab was given to the mice twice weekly. The experiments shown were performed once


原文阅读

https://www.nature.com/articles/s41467-017-00786-z

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