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Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy.
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- Author(s): Lee J;Lee J; Sheen JH; Sheen JH; Lim O; Lim O; Lee Y; Lee Y; Ryu J; Ryu J; Shin D; Shin D; Kim YY; Kim YY; Kim M; Kim M
- Source:
Scientific reports [Sci Rep] 2020 Oct 20; Vol. 10 (1), pp. 17753. Date of Electronic Publication: 2020 Oct 20.- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't- Language:
English - Source:
- Additional Information
- Source: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
- Publication Information: Original Publication: London : Nature Publishing Group, copyright 2011-
- Subject Terms:
- Abstract: As recent advancements in the chimeric antigen receptor-T cells have revolutionized the way blood cancers are handled, potential benefits from producing off-the-shelf, standardized immune cells entail the need for development of allogeneic immune cell therapy. However, host rejection driven by HLA disparity in adoptively transferred allogeneic T cells remains a key obstacle to the universal donor T cell therapy. To evade donor HLA-mediated immune rejection, we attempted to eliminate T cell's HLA through the CRISPR/Cas9 gene editing system. First, we screened 60 gRNAs targeting B2M and multiple sets of gRNA each targeting α chains of HLA-II (DPA, DQA and DRA, respectively) using web-based design tools, and identified specific gRNA sequences highly efficient for target deletion without carrying off-target effects. Multiplex genome editing of primary human T cells achieved by the newly discovered gRNAs yielded HLA-I- or HLA-I/II-deficient T cells that were phenotypically unaltered and functionally intact. The overnight mixed lymphocyte reactions demonstrated the HLA-I-negative cells induced decreased production of IFN-γ and TNF-α in alloreactive T cells, and deficiency of HLA-I/II in T cells further dampened the inflammatory responses. Taken together, our approach will provide an efficacious pathway toward the universal donor cell generation by manipulating HLA expression in therapeutic T cells.
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Science. 2020 Feb 28;367(6481):. (PMID: 32029687) - Accession Number: 0 (HLA Antigens)
- Publication Date: Date Created: 20201021 Date Completed: 20210125 Latest Revision: 20210125
- Publication Date: 20231215
- Accession Number: PMC7576162
- Accession Number: 10.1038/s41598-020-74772-9
- Accession Number: 33082438
- Source:
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