2. Academic Validation
  3. iPSC-Derived Platelets Depleted of HLA Class I Are Inert to Anti-HLA Class I and Natural Killer Cell Immunity

iPSC-Derived Platelets Depleted of HLA Class I Are Inert to Anti-HLA Class I and Natural Killer Cell Immunity

  • Stem Cell Reports. 2020 Jan 14;14(1):49-59. doi: 10.1016/j.stemcr.2019.11.011.
Daisuke Suzuki 1,  Charlotte Flahou 1,  Norihide Yoshikawa 1,  Ieva Stirblyte 1,  Yoshikazu Hayashi 2,  Akira Sawaguchi 3,  Marina Akasaka 1,  Sou Nakamura 1,  Natsumi Higashi 1,  Huaigeng Xu 1,  Takuya Matsumoto 1,  Kosuke Fujio 4,  Markus G Manz 5,  Akitsu Hotta 1,  Hitoshi Takizawa 2,  Koji Eto 6,  Naoshi Sugimoto 7
Affiliations

Affiliations

  • 1 Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
  • 2 International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan.
  • 3 Department of Anatomy, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • 4 Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co. Ltd., Tokushima 771-0192, Japan.
  • 5 Department of Hematology, University and University Hospital Zürich, 8091 Zürich, Switzerland.
  • 6 Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan; Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. Electronic address: kojieto@cira.kyoto-u.ac.jp.
  • 7 Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. Electronic address: naoshi.sugi@cira.kyoto-u.ac.jp.
PMID: 31883921 DOI: 10.1016/j.stemcr.2019.11.011
Abstract

The ex vivo production of platelets depleted of human leukocyte antigen class I (HLA-I) could serve as a universal measure to overcome platelet transfusion refractoriness caused by HLA-I incompatibility. Here, we developed human induced pluripotent cell-derived HLA-I-deficient platelets (HLA-KO iPLATs) in a clinically applicable imMKCL system by genetic manipulation and assessed their immunogenic properties including natural killer (NK) cells, which reject HLA-I downregulated cells. HLA-KO iPLATs were deficient for all HLA-I but did not elicit a cytotoxic response by NK cells in vitro and showed circulation equal to wild-type iPLATs upon transfusion in our newly established Hu-NK-MSTRG mice reconstituted with human NK cells. Additionally, HLA-KO iPLATs successfully circulated in an alloimmune platelet transfusion refractoriness model of Hu-NK-MISTRG mice. Mechanistically, the lack of NK cell-activating ligands on platelets may be responsible for evading the NK cell response. This study revealed the unique non-immunogenic property of platelets and provides a proof of concept for the clinical application of HLA-KO iPLATs.

Keywords

HLA class I; IL-15; MSTRG mice; iPSC; imMKCL; megakaryocyte; natural killer cell; platelet; platelet transfusion; refractoriness; regenerative medicine.

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