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

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.

Expression of glucocorticoid receptor shows negative correlation with human B-cell engraftment in PBMC-transplanted NOGhIL-4-Tg mice

“…As shown in Figure 1B and Figure 2A (upper two panels), no significant difference was observed in the proportions of CD4+ T cells and CD8+ T cells between NOG and NOG-hIL-4 Tg mice with or without immunization, whereas CD19+ B cell levels were significantly higher in NOG-hIL-4-Tg mice than in conventional NOG mice (Figure 2A, lower panel). This result was consistent with our previous report (16). On the other hand, immunized NOG-hIL-4-Tg mice possessed the highest proportion of B cells (17.8%).…”

“…Cg-Prkdc scid il2rγ tm1Sug /ShiJic) mice (3) were purchased from InVivo Science, Inc. (IVS, Kawasaki, Japan). NOG-hIL-4 Tg (formally, NOD.Cg-Prkdc scid il2rγ tm1Sug / ShiJic Tg(CMV-IL4)3-2/Jic) mice (16) were previously generated by CIEA and maintained at Tokai University School of Medicine under specific-pathogen-free (SPF) conditions. The offspring with the inserted transgene were selected as reported previously (16).…”

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

“…We reconstructed human immunity in NOG mice transplanted with HSC and immunized with CH401MAP, a specific HER2 peptide antigen for patients with breast cancer, and keyhole limpet hemocyanin (KLH), or toxic shock syndrome toxin-1 (TSST-1), with Freund's complete adjuvant and measured the specific antibody titer by ELISA. As a result, although antigen-specific IgM and nonspecific IgG were detected in the sera, antigen-specific IgG was not detected in mice (Table 1) [114][115][116]. These mice did not develop a germinal center, which has a structure composed of T, B, and follicular DCs and plays a crucial role in highly specific crass-switched IgG antibody production.…”

“…Therefore, it is difficult to evaluate the production of antigen-specific IgG production after antigen immunization in those mice. To evaluate antigen-specific IgG responses in PBMC-transplanted immunodeficient mice, we developed a novel NOD/Shi-scid-IL2rg null (NOG) mouse strain that systemically expresses the human IL-4 gene (NOG-hIL-4-Tg) [116]. After human PBMC transplantation, GVHD symptoms were significantly suppressed in the Tg NOG, as compared to conventional NOG mice.…”

“…This evidence suggests that the PBMC-transplanted NOG-hIL-4-Tg mouse system is an effective tool to evaluate the production of antigen-specific IgG antibodies, following vaccination in individual cancer patients [116]. The mouse system can be used for the evaluation of the effect of ICIs on antibody production in the presence of human PBMCs, as well.…”