An effective approach to prevent immune rejection of human ESC-derived allografts

Cell Stem Cell. 2014 Jan 2;14(1):121-30. doi: 10.1016/j.stem.2013.11.014.

Abstract

Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection of hESC-derived cells by recipients. Here, we optimized humanized mice (Hu-mice) reconstituted with a functional human immune system that mounts a vigorous rejection of hESCs and their derivatives. We established knockin hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, denoted CP hESCs. We then demonstrated that allogenic CP hESC-derived teratomas, fibroblasts, and cardiomyocytes are immune protected in Hu-mice, while cells derived from parental hESCs are effectively rejected. Expression of both CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway, is required to confer immune protection, as neither was sufficient on their own. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Biomarkers / analysis
  • Blotting, Western
  • Cell Differentiation*
  • Cell Proliferation
  • Cell- and Tissue-Based Therapy*
  • Cells, Cultured
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / immunology*
  • Embryonic Stem Cells / metabolism
  • Fetus / cytology
  • Fetus / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control*
  • Humans
  • Immunoconjugates / genetics
  • Immunoconjugates / metabolism
  • Immunosuppression*
  • Liver / cytology
  • Liver / metabolism
  • Mice
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Teratoma / immunology
  • Teratoma / pathology
  • Teratoma / prevention & control
  • Transplantation, Homologous

Substances

  • B7-H1 Antigen
  • Biomarkers
  • Cd274 protein, mouse
  • Immunoconjugates
  • RNA, Messenger
  • Abatacept