Selective deletion of human leukocyte antigens protects stem cell-derived islets from immune rejection

Cell Rep. 2021 Aug 17;36(7):109538. doi: 10.1016/j.celrep.2021.109538.


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.

Keywords: beta cell replacement therapy; cell therapy; diabetes; human leukocyte antigens; immune evasion; immune rejection; pancreatic beta cells; regenerative medicine; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Line
  • Clone Cells
  • Gene Deletion*
  • Graft Rejection / immunology*
  • HLA Antigens / metabolism*
  • Humans
  • Islets of Langerhans / immunology*
  • Killer Cells, Natural / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Mice, Inbred NOD
  • Pluripotent Stem Cells / cytology*
  • T-Lymphocytes / immunology


  • HLA Antigens