Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II
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Performing Subretinal Injections in Rodents to Deliver Retinal Pigment Epithelium Cells in Suspension
Published on: January 23, 2015
Sandra Petrus-Reurer1, Nerges Winblad2, Pankaj Kumar2
1Clinical Neuroscience, Section for Ophtalmology and Vision, Karolinska Institutet, St. Erik Eye Hospital, 11282 Stockholm, Sweden; Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden.
Abstract:
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.
