CD8++ T cell-mediated rejection of allogenic human-induced pluripotent stem cell-derived cardiomyocyte sheets in human PBMC-transferred NOG MHC double knockout mice

BACKGROUND: Transplantation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) has emerged as a promising therapy to treat end-stage heart failure. However, the immunogenicity of hiPS-CMs in transplanted patients has not been fully elucidated. Thus, in vivo models are required to estimate immune responses against hiPS-CMs in transplant recipients. METHODS: We transferred human peripheral blood mononuclear cells (hPBMCs) into NOD/Shi-scid IL-2rgnull null (NOG) MHC class I/II double knockout (NOG-Delta MHC) mice, which were reported to accept hPBMCs without xenogeneic-graft-versus-host disease (xeno-GVHD). Then, hiPS-CM sheets generated from the hiPS cell line 201B7 harboring a luciferase transgene were transplanted into the subcutaneous space of NOG-Delta MHC mice. Graft survival was monitored by bioluminescent images using a Xenogen In Vivo Imaging System. RESULTS: The human immune cells were engrafted for more than 3 months in NOG-Delta MHC mice without lethal xeno-GVHD. The hiPS-CMs expressed a moderate level of human leukocyte antigen (HLA)-class I, but not HLA-class II, molecules even after interferon-gamma (IFN-gamma) stimulation. Consistently, the allogenic IFN-gamma-treated hiPS-CMs induced weak CD8+ + but not CD4+ + T cell responses in vitro. hiPS-CM sheets disappeared approximately 17 to 24 days after transplantation in hPBMCtransferred NOG-Delta MHC mice, and CD8+ + T cell depletion significantly prolonged graft survival, similar to what was observed following tacrolimus treatment. CONCLUSIONS: hiPS-CMs are less immunogenic in vitro but induce sufficient CD8+ + T cell-mediated immune responses for graft rejection in vivo.