Selective deletion of human leukocyte antigens protects stem cell-derived islets from immune rejection
Open accessAbstract
Stem cell-based replacement therapies hold the promise to restore function of damaged or degenerated tissue such as the pancreatic islets in people with type 1 diabetes. Wide application of these therapies requires overcoming the fundamental roadblock of immune rejection. To address this issue, we use genetic engineering to create human pluripotent stem cells (hPSCs) in which the majority of the polymorphic human leukocyte antigens (HLAs), the main drivers of allogeneic rejection, are deleted. We retain the common HLA class I allele HLA-A2 and less polymorphic HLA-E/F/G to allow immune surveillance and inhibition of natural killer (NK) cells. We employ a combination of in vitro assays and humanized mouse models to demonstrate that these gene manipulations significantly reduce NK cell activity and T-cell-mediated alloimmune response against hPSC-derived islet cells. In summary, our approach produces hypoimmunogenic hPSCs that can be readily matched with recipients to avoid alloimmune rejection.
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hPSCs with HLA-A, B, and C deleted except HLA-A2, retaining HLA-E, and CIITA removed differentiated into SC-islets that demonstrated protection from T-cell mediated rejection and reduced NK immune responses in allogeneic humanized mice.
“These hPSCs could differentiate into SC-islets that demonstrated protection from T-cell mediated rejection and reduced NK immune responses in allogeneic humanized mice.”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [55]
The Introduction and Discussion state that the edited hPSCs differentiated into insulin-producing β-like cells and were protected from T-cell-mediated rejection in a humanized mouse model. The Results report retained HLA-E expression and reduced NK-cell activation, but that response was measured in an in vitro assay, not in the mice; the reduction was observed for a subset of NK cells after IFNγ treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSC-islets can be genetically engineered to both remove antigens that would signal them for destruction by the host immune system and add surface signaling molecules that induce immune tolerance.
“Alternatively, the SC-islets themselves can be genetically engineered to both remove antigens that would signal them for destruction by the host immune system as well as add surface signaling molecules that induce immune tolerance.54,55”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [55]
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- Authors
- Parent, A. V., Faleo, G., Chavez, J., Saxton, M., Berrios, D. I., Kerper, N. R., Tang, Q., & Hebrok, M.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Parent, Audrey V.
- Hebrok, Matthias
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 36
- Issue
- 7
- Pages
- 109538
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC12416289
- OpenAlex
- W3194648368
- Cited by
- 96
- References
- 48
- Citations by year
- 2026: 21 · 2025: 15 · 2024: 18 · 2023: 17 · 2022: 23 · 2021: 2
- FWCI
- 14.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Funders
- Juvenile Diabetes Research Foundation (5-COE-2019-860-S-B)
- Diabetes Research Connection
- National Institutes of Health (P30 DK063720)
- Eli Lilly and Company
- Juvenile Diabetes Research Foundation United Kingdom (2019-019)
- University of California, San Francisco
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- HLA polymorphism, type 1 diabetes, pluripotent stem cells, HLA-A2, natural killer cells, humanized mice
- MeSH terms
- Alleles, Animals, Cell Line, Clone Cells, Graft Rejection, HLA Antigens, Humans, Islets of Langerhans, Killer Cells, Natural, Lymphocyte Activation, Male, T-Lymphocytes, Mice, Inbred NOD, Gene Deletion, Pluripotent Stem Cells, Mice
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