TY - JOUR
T1 - Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro
AU - Ozaki, Masahiro
AU - Iwanami, Akio
AU - Nagoshi, Narihito
AU - Kohyama, Jun
AU - Itakura, Go
AU - Iwai, Hiroki
AU - Nishimura, Soraya
AU - Nishiyama, Yuichiro
AU - Kawabata, Soya
AU - Sugai, Keiko
AU - Iida, Tsuyoshi
AU - Matsubayashi, Kohei
AU - Isoda, Miho
AU - Kashiwagi, Rei
AU - Toyama, Yoshiaki
AU - Matsumoto, Morio
AU - Okano, Hideyuki
AU - Nakamura, Masaya
N1 - Funding Information:
We thank Dr. Akihiko Yoshimura (Keio University) for invaluable comments, Dr. Shinya Yamanaka (Kyoto University) for the human iPSC clone Ff-I01, and Dr. Yoshihiro Kanemura (Osaka National Hospital) for technical advice and discussions. We are also grateful for K. Fukushima, A. Kohzuki, R. Yamaguchi, F. Renault-Mihara, S. Shibata, K. Kitamura, M. Shinozaki, T. Konomi, Y. Kobayashi, M. Takano, S. Tashiro, T. Okubo, K. Kojima, S. Ito, Y. Tanimoto, Y. Hoshino, K. Yasutake and T. Harada, who are members of the spinal cord research team in the Department of Orthopaedic Surgery, Physiology and Rehabilitation Medicine, Keio University School of Medicine. This work was supported by the Research Center Network for Realization of Regenerative Medicine by the Japan Science and Technology Agency (JST) and the Japan Agency for Medical Research and Development (AMED) (grant number 16bm0204001h0004 to H.O. and M.N.), Grant-in-Aid for Scientific Research by Japan Society for the Promotion of Science (grant number 15K10422 to A.I.) and grant by The General Insurance Association of Japan (grant number 15-2B-13 to A.I.). H.O. is a paid scientific advisory board member for SanBio Co., Ltd. The other authors indicated no potential conflicts of interest.
Publisher Copyright:
© 2017 The Authors
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.scr.2017.01.007
DO - 10.1016/j.scr.2017.01.007
M3 - Article
C2 - 28135684
AN - SCOPUS:85010644783
SN - 1873-5061
VL - 19
SP - 128
EP - 138
JO - Stem Cell Research
JF - Stem Cell Research
ER -