We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice.
- Authors
Hu, Xiaomeng; Gattis, Corie; Olroyd, Ari G.; Friera, Annabelle M.; White, Kathy; Young, Chi; Basco, Ron; Lamba, Meghan; Wells, Frank; Ankala, Ramya; Dowdle, William E.; Lin, August; Egenberger, Kyla; Rukstalis, J. Michael; Millman, Jeffrey R.; Connolly, Andrew J.; Deuse, Tobias; Schrepfer, Sonja
- 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. Islets engineered to evade immunity: The need for immunosuppressive drugs is one major roadblock to using pancreatic islet transplantation to treat diabetes. Hu et al. used CRISPR to knock out the genes encoding class I and II MHC and overexpress CD47 in primary human pancreatic islet cells, making them immune-evasive. The hypoimmune cells were reaggregated into pseudoislets and transplanted into diabetic humanized mice. The grafted cells escaped immune-mediated killing and were able to control blood glucose without immunosuppressants. The authors also showed that an anti-CD47 antibody could function as a safety switch in the grafted mice to eliminate the transplanted cells if needed. —CAC
- Subjects
ISLANDS of Langerhans; TYPE 1 diabetes; AUTOIMMUNITY; BLOOD sugar; MICE; DIABETES
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 691, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adg5794