Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II
Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II
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DOI：
10.1016/j.stemcr.2020.02.006
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发表时间：
2020-04-14
影响因子：
5.9
通讯作者：
Lanner, Fredrik
中科院分区：
文献类型：
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作者：
Petrus-Reurer, Sandra;Winblad, Nerges;Lanner, Fredrik
人胚胎干细胞衍生的视网膜色素上皮（hESC-RPE）细胞可以作为老年性黄斑变性晚期的替代疗法。然而，同种异体hESC-RPE移植物引发免疫排斥，支持逃避其免疫识别的策略。我们建立了单敲除β-2微球蛋白（SKO-B2 M）、II类主要组织相容性复合物反式激活因子（SKO-CIITA）和双敲除（DKO）的hESC细胞系，这些细胞系进一步分化为缺乏表面人类白细胞抗原I类（HLA-I）或HLA-II或两者的相应hESC-RPE细胞系。CD 4+和CD 8 + T细胞的活化被hESC-RPE DKO细胞显著降低，而自然杀伤细胞的细胞毒性应答没有增加。在临床前兔模型中移植SKO-B2 M、SKO-CIITA或DKO hESC-RPE后，供体细胞排斥反应减少并延迟。总之，我们已经开发出缺乏HLA-I和-II抗原的细胞系，其在大眼睛动物模型中引起体外T细胞反应降低以及排斥反应降低。
Human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells could serve as a replacement therapy in advanced stages of age-related macular degeneration. However, allogenic hESC-RPE transplants trigger immune rejection, supporting a strategy to evade their immune recognition. We established single-knockout beta-2 microglobulin (SKO-B2M), class II major histocompatibility complex transactivator (SKO-CIITA) and double-knockout (DKO) hESC lines that were further differentiated into corresponding hESC-RPE lines lacking either surface human leukocyte antigen class I (HLA-I) or HLA-II, or both. Activation of CD4+ and CD8+ T-cells was markedly lower by hESC-RPE DKO cells, while natural killer cell cytotoxic response was not increased. After transplantation of SKO-B2M, SKO-CIITA, or DKO hESC-RPEs in a preclinical rabbit model, donor cell rejection was reduced and delayed. In conclusion, we have developed cell lines that lack both HLA-I and -II antigens, which evoke reduced T-cell responses in vitro together with reduced rejection in a large-eyed animal model.