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* Department of Immunogenetics and
Department of Oral and Maxillofacial Surgery, Kumamoto University, Graduate School of Medical Sciences, Kumamoto, Japan;
Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan; and
Japan Science and Technology Agency, CREST, Tokyo, Japan
A method for the genetic modification of dendritic cells (DC) was previously established based on the in vitro differentiation of embryonic stem (ES) cells to DC (ES-DC). The unavailability of human ES cells genetically identical to the patients will be a problem in the future clinical application of this technology. This study attempted to establish a strategy to overcome this issue. The TAP1 or β2-microglobulin (β2m) gene was disrupted in 129 (H-2b)-derived ES cells and then expression vectors for the H-2Kd or β2m-linked form of Kd (β2m-Kd) were introduced, thus resulting in two types of genetically engineered ES-DC, TAP1–/–/Kd ES-DC and β2m–/–/β2m-Kd ES-DC. As intended, both of the transfectant ES-DC expressed Kd but not the intrinsic H-2b haplotype-derived MHC class I. β2m–/–/β2m-Kd and TAP1–/–/Kd ES-DC were not recognized by pre-activated H-2b-reactive CTL and did not prime H-2b reactive CTL in vitro or in vivo. β2m–/–/β2m-Kd ES-DC and TAP1–/–/Kd ES-DC had a survival advantage in comparison to β2m+/–/β2m-Kd ES-DC and TAP1+/+/Kd ES-DC, when transferred into BALB/c mice. Kd-restricted RSV-M2-derived peptide-loaded ES-DC could prime the epitope-specific CTL upon injection into the BALB/c mice, irrespective of the cell surface expression of intrinsic H-2b haplotype-encoded MHC class I. β2m–/–/β2m-Kd ES-DC were significantly more efficient in eliciting immunity against RSV M2 protein-expressing tumor cells than β2m+/–/β2m-Kd ES-DC. The modification of the β2m or TAP gene may therefore be an effective strategy to resolve the problem of HLA class I allele mismatch between human ES or induced pluripotent stem cells and the recipients to be treated.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grants-in-Aid 16590988, 17390292, 17015035, 18014023, 19591172, and 19059012 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases launched as a project commissioned by MEXT, Japan; Research Grant for Intractable Diseases from Ministry of Health and Welfare, Japan; and grants from Japan Science and Technology Agency (JST), the Uehara Memorial Foundation, and the Takeda Science Foundation.
2 Address correspondence and reprint requests to Dr. Satoru Senju, Department of Immunogenetics, Graduate School o f Medical Sciences, Kumamoto University, Honjo 1–1-1, Kumamoto, Japan. E-mail address: senjusat{at}gpo.kumamoto-u.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; ES cell, embryonic stem cell; ES-DC, embryonic stem cell-derived DC; BM-DC, bone marrow-derived DC; β2-microglobulin, β2m; HA, hemagglutinin; RSV, respiratory syncytical virus; PEF, primary mouse embryonic fibroblast; CMTR, chloromethyl-benzoyl-amino-tetramethyl-rhodamine; CMFDA, chlorometylfluorescein diacetate; iPS cell, induced pluripotent stem cell; Luc, luciferase; IRES, Internal ribosomal entry site.
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  S. Senju, M. Haruta, Y. Matsunaga, S. Fukushima, T. Ikeda, K. Takahashi, K. Okita, S. Yamanaka, and Y. Nishimura Characterization of Dendritic Cells and Macrophages Generated by Directed Differentiation from Mouse Induced Pluripotent Stem Cells Stem Cells, May 1, 2009; 27(5): 1021 - 1031. [Abstract] [Full Text] [PDF]
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