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

Ryu Matsumoto; Yin Enzhi; Kazuyoshi Takeda; Kodai Morimoto; Kyoko Yogo; Masaki Harada; Koji Tokushige; Yui Maehara; Saori Hirota; Yuko Kojima; Mamoru Ito; Nagako Sougawa; Shigeru Miyagawa; Yoshiki Sawa; Ko Okumura; Koichiro Uchida

doi:10.1016/j.healun.2024.04.003

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

J Heart Lung Transplant. 2024 Apr 22:S1053-2498(24)01564-X. doi: 10.1016/j.healun.2024.04.003. Online ahead of print.

Authors

Affiliations

¹ Center for Immune Therapeutics and Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
² Center for Immune Therapeutics and Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan.
³ Center for Immune Therapeutics and Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Laboratory of Cell Biology, Research Support Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁴ Laboratory of Morphology and Image Analysis, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁵ Liver Engineering Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kanagawa, Japan.
⁶ Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Physiology, Osaka Dental University, Osaka, Japan.
⁷ Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
⁸ Center for Immune Therapeutics and Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Atopy (Allergy) Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁹ Center for Immune Therapeutics and Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: k-uchida@juntendo.ac.jp.

PMID: 38657776
DOI: 10.1016/j.healun.2024.04.003

Abstract

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-2rg^null (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.

Results: 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.

Conclusions: hiPS-CMs are less immunogenic in vitro but induce sufficient CD8⁺ T cell-mediated immune responses for graft rejection in vivo.

Keywords: CD8+ T cell-mediated rejection; HiPS-CMs; NOG MHC double knockout mice; iPS; xeno-GVHD.