Generation of hypoimmunogenic human pluripotent stem cells
| Autor: | Leonardo M. R. Ferreira, Alana Allen, Xiao Han, Songwei Duan, Jennifer H. R. Kenty, Chad A. Cowan, Jack L. Strominger, Yulei Xia, Douglas A. Melton, Paul J. Franco, Torsten B. Meissner, Preston Hedrick, Mengning Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Pluripotent Stem Cells
Multidisciplinary Innate immune system CD47 T cell Genes MHC Class II Cell Genes MHC Class I Biological Sciences Biology Cell Line Cell biology Cell therapy Gene Knockout Techniques medicine.anatomical_structure Immune system Cell killing medicine Humans CRISPR-Cas Systems Genetic Engineering Induced pluripotent stem cell |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:10441-10446 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1902566116 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|