NOG-hIL-4-Tg, a new humanized mouse model for producing tumor antigen-specific IgG antibody by peptide vaccination.

Yoshie Kametani,Mamoru Ito,Yutaka Tokuda,Yukari Muguruma,Asuka Miyamoto,Ryoji Ito,Yusuke Kikuchi,Kiyoshi Ando,Ikumi Katano,Sonoko Habu,Banri Tsuda,Anne S De Groot

doi:10.1371/journal.pone.0179239

Abstract

Immunodeficient mice transplanted with human peripheral blood mononuclear cells (PBMCs) are promising tools to evaluate human immune responses to vaccines. However, these mice usually develop severe graft-versus-host disease (GVHD), which makes estimation of antigen-specific IgG production after antigen immunization difficult. To evaluate antigen-specific IgG responses in PBMC-transplanted immunodeficient mice, we developed a novel NOD/Shi-scid-IL2rγnull (NOG) mouse strain that systemically expresses the human IL-4 gene (NOG-hIL-4-Tg). After human PBMC transplantation, GVHD symptoms were significantly suppressed in NOG-hIL-4-Tg compared to conventional NOG mice. In kinetic analyses of human leukocytes, long-term engraftment of human T cells has been observed in peripheral blood of NOG-hIL-4-Tg, followed by dominant CD4+ T rather than CD8+ T cell proliferation. Furthermore, these CD4+ T cells shifted to type 2 helper (Th2) cells, resulting in long-term suppression of GVHD. Most of the human B cells detected in the transplanted mice had a plasmablast phenotype. Vaccination with HER2 multiple antigen peptide (CH401MAP) or keyhole limpet hemocyanin (KLH) successfully induced antigen-specific IgG production in PBMC-transplanted NOG-hIL-4-Tg. The HLA haplotype of donor PBMCs might not be relevant to the antibody secretion ability after immunization. These results suggest that the human PBMC-transplanted NOG-hIL-4-Tg mouse is an effective tool to evaluate the production of antigen-specific IgG antibodies.

Highlights

To develop molecular targeting reagents, an evaluation system of safety and efficacy is essential
We examined whether xeno-graft-versus-host disease (GVHD) is suppressed in peripheral blood mononuclear cells (PBMCs)-NOG-hIL-4-Tg compared with the conventional NOG mice
These results suggest that B cell function is maintained in PBMC-NOG-hIL-4-Tg and that antigen-specific antibody production can be monitored by this system irrespective of the HLA type

Summary

Introduction

To develop molecular targeting reagents, an evaluation system of safety and efficacy is essential. The evaluation of a vaccine response is impossible because rodents lack orthologs of human major histocompatibility complex (MHC) and show low homology among TCR repertoires [4,5]. These models are insufficient to evaluate human immune responses [6], and eventually it will be necessary to evaluate the efficacy and toxicity of vaccination based on human immunity. In HSC-transplanted humanized mice, human T cell responses and antigen-specific IgG production are impaired because murine MHC-restricted human T cells fail to interact with human B cells, HLA-transgenic (Tg) humanized mice show somewhat improved responses [13,14,15]. We established a novel strain of NOG mice in which human IL-4, a representative Th2 cytokine, is systemically expressed, and examined whether this mouse strain can support antigen-specific human antibody production in response to HER2 peptide vaccination

Ethical approval

Results

Discussion