Generation of hypoimmunogenic human pluripotent stem cells

Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-05, Vol.116 (21), p.10441-10446
Main Authors: Han, Xiao, Wang, Mengning, Duan, Songwei, Franco, Paul J., Kenty, Jennifer Hyoje-Ryu, Hedrick, Preston, Xia, Yulei, Allen, Alana, Ferreira, Leonardo M. R., Strominger, Jack L., Melton, Douglas A., Meissner, Torsten B., Cowan, Chad A.
Format: Article
Language:English
Subjects:
Ablation
Adaptive control
Adaptive immunity
Biological Sciences
Cell Line
CRISPR-Cas Systems
Gene expression
Gene Knockout Techniques
Genes, MHC Class I
Genes, MHC Class II
Genetic Engineering - methods
Genomes
Histocompatibility antigen HLA
Humans
Immunity
Immunoassays
Immunomodulation
Immunosurveillance
Innate immunity
Lymphocytes
Lymphocytes T
Macrophages
Natural killer cells
PD-L1 protein
Pluripotency
Pluripotent Stem Cells - immunology
Stem cells
Therapy
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Summary:Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B/-C and HLA class II in human pluripotent stem cells. Furthermore, to prevent innate immune rejection and further suppress adaptive immune responses, we expressed the immunomodulatory factors PD-L1, HLA-G, and the macrophage “don’t-eat me” signal CD47 from the AAVS1 safe harbor locus. Utilizing in vitro and in vivo immunoassays, we found that T cell responses were blunted. Moreover, NK cell killing and macrophage engulfment of our engineered cells were minimal. Our results describe an approach that effectively targets adaptive as well as innate immune responses and may therefore enable cell therapy on a broader scale.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1902566116