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

PLoS One. 2017 Jun 15;12(6):e0179239. doi: 10.1371/journal.pone.0179239. eCollection 2017.

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.

MeSH terms

  • Animals
  • Antibodies, Neoplasm / genetics
  • Antibodies, Neoplasm / immunology*
  • Antibody Formation*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Heterografts
  • Humans
  • Immunization*
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology*
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • Peptides / immunology
  • Peptides / pharmacology*
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / pharmacology*
  • Th2 Cells / immunology
  • Th2 Cells / transplantation

Substances

  • Antibodies, Neoplasm
  • Carrier Proteins
  • IL4 protein, human
  • Immunoglobulin G
  • Peptides
  • noggin protein
  • Interleukin-4
  • ERBB2 protein, human
  • Receptor, ErbB-2

Grants and funding

This work was supported by Japan Society for the Promotion of Science by a Grant-in-Aid for Scientific Research (ITO) (S) [grant number 22220007] to MI; a Tokai University Grant-in-aid Aid to YK (2013–2014); and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2012–2016). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.