An animal model of adult T-cell leukemia: humanized mice with HTLV-1-specific immunity

Blood. 2014 Jan 16;123(3):346-55. doi: 10.1182/blood-2013-06-508861. Epub 2013 Nov 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / metabolism
  • Bone Marrow / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • Cell Separation
  • Disease Models, Animal*
  • Female
  • Fetal Blood / metabolism
  • Flow Cytometry
  • Glycoproteins / metabolism
  • HTLV-I Infections / immunology*
  • Hematopoietic Stem Cells / cytology
  • Human T-lymphotropic virus 1 / immunology
  • Humans
  • Inflammation
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Leukemia-Lymphoma, Adult T-Cell / immunology*
  • Leukemia-Lymphoma, Adult T-Cell / virology
  • Mice
  • Mice, Inbred NOD
  • Peptides / metabolism
  • Spleen / cytology
  • Stem Cells / cytology
  • Viral Load

Substances

  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • Interleukin-2 Receptor alpha Subunit
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse