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-Ideficient 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.
Human induced pluripotent stem cells (iPSCs) can be limitlessly expanded and differentiated into almost all cell types. Moreover, they are amenable to gene manipulation and, because they are established from somatic cells, can be established from essentially any person. Based on these characteristics, iPSCs have been extensively studied as cell sources for tissue grafts, blood transfusions and cancer immunotherapies, and related clinical trials have started. From an immune-matching perspective, autologous iPSCs are perfectly compatible in principle, but also require a prolonged time for reaching the final products, have high cost, and person-to-person variation hindering their common use. Therefore, certified iPSCs with reduced immunogenicity are expected to become off-the-shelf sources, such as those made from human leukocyte antigen (HLA)-homozygous individuals or genetically modified for HLA depletion. Preclinical tests using immunodeficient mice reconstituted with a human immune system (HIS) serve as an important tool to assess the human alloresponse against iPSC-derived cells. Especially, HIS mice reconstituted with not only human T cells but also human natural killer (NK) cells are considered crucial. NK cells attack so-called “missing self” cells that do not express self HLA class I, which include HLA-homozygous cells that express only one allele type and HLA-depleted cells. However, conventional HIS mice lack enough reconstituted human NK cells for these tests. Several measures have been developed to overcome this issue including the administration of cytokines that enhance NK cell expansion, such as IL-2 and IL-15, the administration of vectors that express those cytokines, and genetic manipulation to express the cytokines or to enhance the reconstitution of human myeloid cells that express IL15R-alpha. Using such HIS mice with enhanced human NK cell reconstitution, alloresponses against HLA-homozygous and HLA-depleted cells have been studied. However, most studies used HLA-downregulated tumor cells as the target cells and tested in vitro after purifying human cells from HIS mice. In this review, we give an overview of the current state of iPSCs in cell therapies, strategies to lessen their immunogenic potential, and then expound on the development of HIS mice with reconstituted NK cells, followed by their utilization in evaluating future universal HLA-engineered iPSC-derived cells.
La production in vitro de plaquettes offre une opportunité de résoudre les problèmes liés aux limitations d’approvisionnement et à la sécurité des dons de produits dérivés du sang. Les cellules souches pluripotentes induites – ou iPSC – sont une source idéale pour la production de cellules à des fins de thérapies régénératives. Nous avons précédemment établi avec succès une lignée mégacaryocytaire immortalisée à partir d’iPSC. Celle-ci possède une capacité de prolifération fiable. Par ailleurs, il est possible de les cryoconserver. Elle est donc une source adaptée de cellules primaires pour la production de plaquettes suivant les Bonnes Pratiques de Fabrication (BPF). Dans le même temps, la capacité améliorée des bioréacteurs à reproduire certaines conditions physiologiques, telle que la turbulence, de pair avec la découverte de molécules favorisant la thrombopoïèse, a contribué à l’accomplissement de la production de plaquettes en quantité et qualité suffisantes pour répondre aux besoins cliniques. La production de plaquettes à partir de cellules iPS s’étend aussi aux patients en état de réfraction allo-immune, par la production de plaquettes autologues ou dont on a génétiquement manipulé l’expression des Antigènes des Leucocytes Humains (HLA) et des Antigènes Plaquettaires Humain (HPA). Considérant ces avancées fondamentales, les plaquettes iPSC avec expression des HLA modifiées se présentent comme un potentiel produit de transfusion universel. Dans cette revue, nous souhaitons apporter une vue d’ensemble de la production in vitro de plaquettes à partir de cellules iPS, et de son possible potentiel transformatif, d’importance capitale dans le domaine de la transfusion des produits sanguins.
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