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

• Published in: The Journal of heart and lung transplantation Vol. 43; no. 8; pp. 1348 - 1357
• Main Authors: Matsumoto, Ryu, Enzhi, Yin, Takeda, Kazuyoshi, Morimoto, Kodai, Yogo, Kyoko, Harada, Masaki, Tokushige, Koji, Maehara, Yui, Hirota, Saori, Kojima, Yuko, Ito, Mamoru, Sougawa, Nagako, Miyagawa, Shigeru, Sawa, Yoshiki, Okumura, Ko, Uchida, Koichiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024
• Subjects: CD8+ T cell-mediated rejection; HiPS-CMs; iPS; NOG MHC double knockout mice; xeno-GVHD; NOG MHC double knockout mice; HiPS-CMs; iPS; CD8+ T cell-mediated rejection; xeno-GVHD; hiPS-CMs
• ISSN: 1053-2498; 1557-3117; 1557-3117
• DOI: 10.1016/j.healun.2024.04.003

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. We transferred human peripheral blood mononuclear cells (hPBMCs) into NOD/Shi-scid IL-2rgnull (NOG) MHC class I/II double knockout (NOG-ΔMHC) 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-ΔMHC mice. Graft survival was monitored by bioluminescent images using a Xenogen In Vivo Imaging System. The human immune cells were engrafted for more than 3 months in NOG-ΔMHC 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-γ) stimulation. Consistently, the allogenic IFN-γ-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 hPBMC-transferred NOG-ΔMHC mice, and CD8+ T cell depletion significantly prolonged graft survival, similar to what was observed following tacrolimus treatment. hiPS-CMs are less immunogenic in vitro but induce sufficient CD8+ T cell-mediated immune responses for graft rejection in vivo.