Ozaki Masahiro, Iwanami Akio, Nagoshi Narihito, Kohyama Jun, Itakura Go, Iwai Hiroki, Nishimura Soraya, Nishiyama Yuichiro, Kawabata Soya, Sugai Keiko, Iida Tsuyoshi, Matsubayashi Kohei, Isoda Miho, Kashiwagi Rei, Toyama Yoshiaki, Matsumoto Morio, Okano Hideyuki, Nakamura Masaya
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan; Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
Stem Cell Res. 2017 Mar;19:128-138. doi: 10.1016/j.scr.2017.01.007. Epub 2017 Jan 19.
To achieve the goal of a first-in-human trial for human induced pluripotent stem cell (hiPSC)-based transplantation for the treatment of various diseases, allogeneic human leukocyte antigen (HLA)-matched hiPSC cell banks represent a realistic tool from the perspective of quality control and cost performance. Furthermore, considering the limited therapeutic time-window for acute injuries, including neurotraumatic injuries, an iPS cell bank is of potential interest. However, due to the relatively immunoprivileged environment of the central nervous system, it is unclear whether HLA matching is required in hiPSC-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation for the treatment of neurodegenerative diseases and neurotraumatic injuries. In this study, we evaluated the significance of HLA matching in hiPSC-NS/PC transplantation by performing modified mixed lymphocyte reaction (MLR) assays with hiPSC-NS/PCs. Compared to fetus-derived NS/PCs, the expression levels of human leukocyte antigen-antigen D related (HLA-DR) and co-stimulatory molecules on hiPSC-NS/PCs were significantly low, even with the addition of tumor necrosis factor-α (TNFα) and/or interferon-γ (IFNγ) to mimic the inflammatory environment surrounding transplanted hiPSC-NS/PCs in injured tissues. Interestingly, both the allogeneic HLA-matched and the HLA-mismatched responses were similarly low in the modified MLR assay. Furthermore, the autologous response was also similar to the allogeneic response. hiPSC-NS/PCs suppressed the proliferative responses of allogeneic HLA-mismatched peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Thus, the low antigen-presenting function and immunosuppressive effects of hiPSC-NS/PCs result in a depressed immune response, even in an allogeneic HLA-mismatched setting. It is crucial to verify whether these in vitro results are reproducible in a clinical setting.
为实现基于人诱导多能干细胞（hiPSC）移植治疗各种疾病的首次人体试验目标，从质量控制和性价比角度来看，同种异体人白细胞抗原（HLA）匹配的hiPSC细胞库是一种切实可行的工具。此外，考虑到包括神经创伤性损伤在内的急性损伤的治疗时间窗有限，诱导多能干细胞库具有潜在意义。然而，由于中枢神经系统相对免疫赦免的环境，尚不清楚在hiPSC衍生的神经干/祖细胞（hiPSC-NS/PC）移植治疗神经退行性疾病和神经创伤性损伤时是否需要HLA匹配。在本研究中，我们通过对hiPSC-NS/PC进行改良混合淋巴细胞反应（MLR）试验，评估了HLA匹配在hiPSC-NS/PC移植中的意义。与胎儿来源的NS/PC相比，即使添加肿瘤坏死因子-α（TNFα）和/或干扰素-γ（IFNγ）以模拟受损组织中移植的hiPSC-NS/PC周围的炎症环境，hiPSC-NS/PC上人类白细胞抗原-D相关（HLA-DR）和共刺激分子的表达水平仍显著较低。有趣的是，在改良MLR试验中，同种异体HLA匹配和HLA不匹配的反应同样较低。此外，自体反应也与同种异体反应相似。hiPSC-NS/PC以剂量依赖的方式抑制同种异体HLA不匹配的外周血单个核细胞（PBMC）的增殖反应。因此，hiPSC-NS/PC的低抗原呈递功能和免疫抑制作用导致免疫反应受到抑制，即使在同种异体HLA不匹配的情况下也是如此。验证这些体外结果在临床环境中是否可重复至关重要。
