In Vivo Murine-Matured Human CD3+ Cells as a Preclinical Model for T Cell-Based Immunotherapies
In Vivo Murine-Matured Human CD3+ Cells as a Preclinical Model for T Cell-Based Immunotherapies
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DOI：
10.1016/j.omtm.2017.05.004
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发表时间：
2017-09-01
影响因子：
4.7
通讯作者：
Kiem, Hans-Peter
中科院分区：
文献类型：
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作者：
Haworth, Kevin G.;Ironside, Christina;Kiem, Hans-Peter
免疫细胞疗法是一种治疗广泛的恶性和感染性疾病的有前途和强大的方法。虽然细胞免疫疗法的概念最初是在20世纪90年代提出的，但直到最近几年才成功地应用于临床。尽管在创建针对恶性和病毒表位的工程化受体方面取得了重大进展，但不存在用于快速测试和直接比较这些工程化受体的有效临床前动物模型。在小鼠中使用成熟的人类T细胞通常会导致移植物抗宿主病（GvHD），这严重限制了此类研究的有效性。或者，成人单采CD 34（+）细胞移植到新生儿非肥胖糖尿病（NOD）-严重联合免疫缺陷（SCID）-常见γ链（-/-）（NSG）小鼠中，并导致外周循环中CD 3（+）T细胞的发育。我们证明，这些来自人类的体内鼠成熟自体CD 3（+）T细胞（MATCH）可以从小鼠中收集，用慢病毒载体改造，再输注到小鼠体内，并在注射后50天内以稳定的水平在多个淋巴区室中检测到。与从人类供体收集的自体CD 3（+）细胞不同，这些MATCH小鼠在T细胞给药后没有表现出GvHD。这种新的小鼠模型提供了在临床前环境中筛选不同的基于免疫疗法的治疗的机会。
Adoptive cellular immunotherapy is a promising and powerful method for the treatment of a broad range of malignant and infectious diseases. Although the concept of cellular immunotherapy was originally proposed in the 1990s, it has not seen successful clinical application until recent years. Despite significant progress in creating engineered receptors against both malignant and viral epitopes, no efficient preclinical animal models exist for rapidly testing and directly comparing these engineered receptors. The use of matured human T cells in mice usually leads to graft-versus-host disease (GvHD), which severely limits the effectiveness of such studies. Alternatively, adult apheresis CD34(+) cells engraft in neonatal non-obese diabetic (NOD)-severe combined immunodeficiency (SCID)-common gamma chain(-/-)(NSG) mice and lead to the development of CD3(+) T cells in peripheral circulation. We demonstrate that these in vivo murine-matured autologous CD3(+) T cells from humans (MATCH) can be collected from the mice, engineered with lentiviral vectors, reinfused into the mice, and detected in multiple lymphoid compartments at stable levels over 50 days after injection. Unlike autologous CD3(+) cells collected from human donors, these MATCH mice did not exhibit GvHD after T cell administration. This novel mouse model offers the opportunity to screen different immunotherapy-based treatments in a preclinical setting.