The neutralizing function of the anti-HTLV-1 antibody is essential in preventing in vivo transmission of HTLV-1 to human T cells in NOD-SCID/γcnull (NOG) mice.

Mineki Saito,Hideki Fujii,Yoshiaki Takahashi,Toshio Matsuzaki,Hiroshi Takashima,Akira Kodama,Yuetsu Tanaka,Reiko Tanaka

doi:10.1186/s12977-014-0074-z

Abstract

BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) causes both neoplastic and inflammatory diseases, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Because these life-threatening and disabling diseases are not yet curable, it is important to prevent new HTLV-1 infections.FindingsIn this study, we have established a simple humanized mouse model of HTLV-1 infection for evaluating prophylactic and therapeutic interventions. In this model, HTLV-1-negative normal human peripheral blood mononuclear cells (PBMCs) are transplanted directly into the spleens of severely immunodeficient NOD-SCID/γcnull (NOG) mice, together with mitomycin-treated HTLV-1-producing T cells. Using this model, we tested the efficacy of monoclonal antibodies (mAbs) specific to HTLV-1 as well as human IgG isolated from HAM/TSP patients (HAM-IgG) in preventing HTLV-1-infection. One hour before and 24 h after transplantation of the human cells, each antibody sample was inoculated intraperitoneally. On day 14, human PBMCs isolated from the mouse spleens were tested for HTLV-1 infection. Whereas fresh CD4-positive and CD8-positive T cells isolated from untreated mice or mice treated with isotype control mAb, HTLV-1 non-neutralizing mAbs to envelope gp46, gag p19, and normal human IgG were all infected with HTLV-1; the mice treated with either HTLV-1 neutralizing anti-gp46 mAb or HAM-IgG did not become infected.ConclusionsOur data indicate that the neutralizing function of the antibody, but not the antigen specificity, is essential for preventing the in vivo transmission of HTLV-1. The present animal model will also be useful for the in vivo evaluation of the efficacy of candidate molecules to be used as prophylactic and therapeutic intervention against HTLV-1 infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-014-0074-z) contains supplementary material, which is available to authorized users.

Highlights

Human T-cell leukemia virus type 1 (HTLV-1) causes both neoplastic and inflammatory diseases, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
HTLV-1-negative healthy human peripheral blood mononuclear cells (PBMCs) (2 × 106/mouse) were transplanted directly into the spleens of severely immunodeficient NOD-SCID/γcnull (NOG) mice, together with cells from the mitomycin C (MMC)-treated HTLV-1infected cell line ILT-M1 (1 × 106/mouse), which is an IL2-dependent CD8+ T cell line derived from a HAM/TSP patient
As previously reported [11], the severe immune deficiency of the NOG strain enables efficient engraftment of the human T cells, and a reduction in mouse death caused by severe graft-versus-host disease (GVHD), compared to those inoculated into the peritoneal cavity, which is the more common route of administration

Summary

Introduction

Human T-cell leukemia virus type 1 (HTLV-1) causes both neoplastic and inflammatory diseases, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The increased numbers of human T cells in the mouse spleens within two weeks after inoculation may have been caused by xenoreactive lymphocyte proliferation, since recent report by Søndergaard et al suggested that injection of human PBMCs into NOG mice cause polyclonal expansion and activation of functional human T cells [12].

Results

Conclusion