1. CD8 + T cell-mediated rejection of allogenic human-induced pluripotent stem cell-derived cardiomyocyte sheets in human PBMC-transferred NOG MHC double knockout mice.
- Author
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Matsumoto R, Enzhi Y, Takeda K, Morimoto K, Yogo K, Harada M, Tokushige K, Maehara Y, Hirota S, Kojima Y, Ito M, Sougawa N, Miyagawa S, Sawa Y, Okumura K, and Uchida K
- Subjects
- Animals, Humans, Mice, Disease Models, Animal, Graft Survival, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, CD8-Positive T-Lymphocytes immunology, Graft Rejection immunology, Induced Pluripotent Stem Cells, Leukocytes, Mononuclear, Myocytes, Cardiac
- 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., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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