title: Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan; Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ozaki
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Iwanami
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Narihito
authors.initials: N
authors.lastname: Nagoshi
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kohyama
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan; Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Itakura
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwai
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Soraya
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nishiyama
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Soya
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sugai
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iida
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsubayashi
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan; Regenerative and Cellular Medicine Office, Sumitomo Dainippon Pharma Co., Ltd., Kobe, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Isoda
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Kashiwagi
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan. Electronic address: hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan. Electronic address: masa@keio.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005333:Fetus / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D058953:Neural Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D006684:HLA-DR Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: HLA; Immunomodulatory function; Mixed lymphocyte reaction; iPS cell-derived neural stem/progenitor cells