title: Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice.
abstract: Induction of specific immune response against therapy-resistant tumor cells can potentially improve clinical outcomes in malignancies. To optimize immunotherapy in the clinic, we aimed to create an in vivo model enabling us to analyze human cytotoxic T-lymphocyte (CTL) responses against human malignancies. To this end, we developed NOD/SCID/IL2rgKO (NSG) mice expressing the HLA class I molecules HLA-A*0201 and A*2402. In the bone marrow (BM) and spleen of HLA class I transgenic (Tg) NSG mice transplanted with cord blood hematopoietic stem cells (HSCs), we found human memory CD8(+) T cells and antigen-presenting cells. To evaluate antigen-specific human CTL responses, we immunized HLA class I Tg NSG mice using polyinosinic:polycytidylic acid mixed Wilms tumor 1 (WT1) peptides, with or without WT1 peptide-loaded autologous dendritic cells. After immunization, the frequencies of HLA-restricted WT1-specific CTLs increased significantly in the spleen. Next, we transplanted the WT1-specific T-cell receptor (WT1-TCR) gene-transduced human HSCs into HLA class I Tg NSG newborn mice. WT1 tetramer-positive CD8(+) T cells differentiated from WT1-TCR-transduced HSCs in the recipients' BM, spleen, and thymus. Upon stimulation with WT1 peptide in vitro, these CTLs produced interferon-γ and showed lytic activity against leukemia cells in an antigen-specific, HLA-restricted manner. HLA class I Tg NSG xenografts may serve as a preclinical model to develop effective immunotherapy against human malignancies.
authors.affiliation: Laboratory for Human Disease Models and.
authors.forename: Yuho
authors.initials: Y
authors.lastname: Najima
authors.affiliation: Laboratory for Human Disease Models and.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomizawa-Murasawa
authors.affiliation: Laboratory for Human Disease Models and.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Laboratory for Human Disease Models and.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Ono
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan; and.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Laboratory for Human Disease Models and.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME.
authors.forename: Leonard D
authors.identifier: http://orcid.org/0000-0002-4868-1031
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan; and.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Laboratory for Human Disease Models and.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000378:metabolism; D059871:HLA-A24 Antigen / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D020014:K562 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: C435939:HLA-A*02:01 antigen; C438506:HLA-A*24:02 antigen; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D025721:WT1 Proteins; C583751:WT1 protein, human