Article ; Online: Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice.
Science translational medicine
2023 Volume 15, Issue 691, Page(s) eadg5794
Abstract: Transplantation of allogeneic pancreatic donor islets has successfully been performed in selected patients with difficult-to-control insulin-dependent diabetes and impaired awareness of hypoglycemia (IAH). However, the required systemic immunosuppression ...
| Abstract | Transplantation of allogeneic pancreatic donor islets has successfully been performed in selected patients with difficult-to-control insulin-dependent diabetes and impaired awareness of hypoglycemia (IAH). However, the required systemic immunosuppression associated with this procedure prevents this cell replacement therapy from more widespread adoption in larger patient populations. We report the editing of primary human islet cells to the hypoimmune HLA class I- and class II-negative and CD47-overexpressing phenotype and their reaggregation into human HIP pseudoislets (p-islets). Human HIP p-islets were shown to survive, engraft, and ameliorate diabetes in immunocompetent, allogeneic, diabetic humanized mice. HIP p-islet cells were further shown to avoid autoimmune killing in autologous, diabetic humanized autoimmune mice. The survival and endocrine function of HIP p-islet cells were not impaired by contamination of unedited or partially edited cells within the p-islets. HIP p-islet cells were eliminated quickly and reliably in this model using a CD47-targeting antibody, thus providing a safety strategy in case HIP cells exert toxicity in a future clinical setting. Transplantation of human HIP p-islets for which no immunosuppression is required has the potential to lead to wider adoption of this therapy and help more diabetes patients with IAH and history of severe hypoglycemic events to achieve insulin independence. |
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| MeSH term(s) | Humans ; Animals ; Mice ; CD47 Antigen ; Islets of Langerhans Transplantation/methods ; Autoimmunity ; Islets of Langerhans ; Diabetes Mellitus, Type 1/therapy ; Insulin ; Hematopoietic Stem Cell Transplantation |
| Chemical Substances | CD47 Antigen ; Insulin |
| Language | English |
| Publishing date | 2023-04-12 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2518854-9 |
| ISSN | 1946-6242 ; 1946-6234 |
| ISSN (online) | 1946-6242 |
| ISSN | 1946-6234 |
| DOI | 10.1126/scitranslmed.adg5794 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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