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.

消耗掉人类白细胞抗原I类（HLA-1）的血小板的离体生产可作为克服因HLA-1不相容引起的血小板输注不应性的通用措施。在这里，我们通过基因操作在临床适用的imMKCL系统中开发了人类诱导的多能细胞衍生的HLA-I缺陷型血小板（HLA-KO iPLAT），并评估了其免疫原性，包括天然杀伤（NK）细胞，该细胞可抑制HLA-1的下调细胞。HLA-KO iPLAT对所有HLA-1均缺乏，但在体外未引起NK细胞的细胞毒性反应并在我们新建立的用人NK细胞重建的Hu-NK-MSTRG小鼠中显示了与野生型iPLAT相同的血液循环。另外，HLA-KO iPLATs在Hu-NK-MISTRG小鼠的同种免疫血小板输注难治性模型中成功传播。从机理上讲，血小板上缺乏NK细胞活化配体可能是逃避NK细胞反应的原因。这项研究揭示了血小板独特的非免疫原性，并为HLA-KO iPLAT的临床应用提供了概念证明。