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.
- 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: [email protected].
- 7. Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. Electronic address: [email protected].
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.