Graft survival of major histocompatibility complex deficient stem cell-derived retinal cells

Abstract

Gene editing of immunomodulating molecules is a potential transplantation strategy to control immune rejection. As we noticed the successful transplantation of retinal pigment epithelium (RPE) derived from embryonic stem cells of a cynomolgus monkey that accidentally lacked MHC class II (MHC-II) molecules, we hypothesized immune rejection could be evaded by suppressing MHC-II. Gene editing by the Crispr/Cas9 system was performed in induced pluripotent stem cells derived from a cynomolgus monkey (miPSCs) for targeted deletion of the gene coding class II MHC trans-activator (CIITA). Then the CIITA-knocked out miPSCs were differentiated into RPE cells to generate miPSC-derived MHC-II knockout RPE. The MHC-II knockout or wild-type RPEs were transplanted into the eyes of healthy cynomolgus monkeys. All monkeys used in this study were male. Here we show when MHC-II knockout RPE are transplanted into monkey eyes, they show suppressed immunogenicity with no infiltration of inflammatory cells, leading to successful engraftment. Our results reasonably evidence the efficacy of MHC-II knockout iPSC-RPE transplants for clinical application. Transplantation of healthy cells can be used to treat irreversibly damaged organs. However, a concern is that the transplanted cells will be rejected by the immune system. Generally, the immune system protects our body when unknown materials invade. But this is undesirable during cell transplantation as the transplanted cells are often eliminated by the host’s immune cells. We demonstrated in monkeys that deletion of part of the immune system in cells prior to transplantation reduced the amount of immune system activity following transplantation. Using similar strategies in the future could enable cell transplants to be used more successfully in humans, making cell transplantation therapy safer and applicable to a wider number of patients. Ishida et al. transplant Crispr/Cas9 gene edited MHC-II knockout or wild-type retinal pigment epithelium into cynomolgus monkey eyes. MHC-II knockout RPE engraft successfully with no infiltration of inflammatory cells.