title: An animal model of adult T-cell leukemia: humanized mice with HTLV-1-specific immunity.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis. To elucidate ATL pathogenesis in vivo, a variety of animal models have been established; however, the mechanisms driving this disorder remain poorly understood due to deficiencies in each of these animal models. Here, we report a novel HTLV-1-infected humanized mouse model generated by intra-bone marrow injection of human CD133(+) stem cells into NOD/Shi-scid/IL-2Rγc null (NOG) mice (IBMI-huNOG mice). Upon infection, the number of CD4(+) human T cells in the periphery increased rapidly, and atypical lymphocytes with lobulated nuclei resembling ATL-specific flower cells were observed 4 to 5 months after infection. Proliferation was seen in both CD25(-) and CD25(+) CD4 T cells with identical proviral integration sites; however, a limited number of CD25(+)-infected T-cell clones eventually dominated, indicating an association between clonal selection of infected T cells and expression of CD25. Additionally, HTLV-1-specific adaptive immune responses were induced in infected mice and might be involved in the control of HTLV-1-infected cells. Thus, the HTLV-1-infected IBMI-huNOG mouse model successfully recapitulated the development of ATL and may serve as an important tool for investigating in vivo mechanisms of ATL leukemogenesis and evaluating anti-ATL drug and vaccine candidates.
authors.affiliation: Department of Microbiology, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Tezuka
authors.forename: Runze
authors.initials: R
authors.lastname: Xun
authors.forename: Mami
authors.initials: M
authors.lastname: Tei
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ueno
authors.forename: Masakazu
authors.initials: M
authors.lastname: Tanaka
authors.forename: Norihiro
authors.initials: N
authors.lastname: Takenouchi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Fujisawa
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism; D015490:HTLV-I Infections / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology; D006801:Humans; D007249:Inflammation; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D019562:Viral Load
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D053645:Interleukin-2 Receptor alpha Subunit; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse