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DOI: 10.1055/s-0030-1269180
Generation of genetically engineered low-antigenicity MHC I knock-down human embryonic stem cells to prevent immune rejection
Introduction: We show that pluripotent of human embryonic stem cells (hESC), in contrary to former beliefs, are not sufficiently immune privileged and undergo immune rejection after transplantation. To overcome this fundamental hurdle of hESC transplantation, we sought to generate a hESC line with reduced antigenicity that would be spared from a host immune response.
Methods and results: MHC I surface expression increased with differentiation state in the order hESC< hEB< hCM. All cells were negative for MHC II. The hESC-line was stably transduced to express firefly luciferase for in vivo bioluminescence imaging (BLI). 1′106 hESC were transplanted into the thigh muscle of WT Balb/C or immunodeficient Balb/C nude mice. Despite their relatively low MHC I expression, hESC were completely rejected within 7±1 days in WT mice, but not in nude mice, confirming the immunologic nature of their cell death. Immunocompetent Balb/C mice mounted a combined cellular and humoral immune response against hESC, as demonstrated by ELISPOT assays and the determination of hESC-specific antibodies, respectively. hESC-MHC I expression was targeted on the transcriptional and translational level. MHC I surface expression on these genetically engineered hESC (ge-hESC) was successfully reduced after 36h. Transplantation of ge-hESC did not result in cell rejection in Balb/C mice and BLI confirmed steady cell signals for an observation period of 42 days. Only minor host cellular and no humoral immune activation was found.
Conclusion: Such barely immunogenic stem cell lines will be crucial for the success of future tissue regenerative approaches.