Journal Article

Human interleukin-4-dependent facilitation of human IgG production in PBL-NOG-hIL-4-Tg mice

Shiina, Takashi, Yamada, Soga, Miyamoto, Asuka, Kirigaya, Daiki, Ito, Ryoji, Ohno, Yusuke, Suzuki-Ohno, Mao, Kojima, Mika, Nakamura, Yukio, Miyazawa, Mariko, Kulski, Jerzy K., Mabuchi, Tomotaka, Kametani, Yoshie, Kikuchi, Yusuke, Shimizu, Tomoka, Yasuda, Atsushi, Hoshino, Yuki, Kashiwagi, Hirofumi, Ohki, Rentaro, Ohshima, Shino, Ishimoto, Hitoshi, Katano, Nagi, Nakada, Shunsuke, Hirota, Ayako, Tsuda, Banri

2025

Overview

Immune-humanized mouse models are indispensable tools for evaluating human immune responses and testing immune-based therapies; however, the induction of robust human antigen-specific immunoglobulin G (IgG) production remains limited due to species-specific incompatibilities. To investigate how human interleukin-4 (IL-4) promotes antibody responses, we employed NOG-hIL-4 transgenic mice (NOG-hIL-4-Tg), which constitutively express human IL-4, and transplanted them with human peripheral blood mononuclear cells (PBMCs). Flow cytometry, histological analysis, and next-generation sequencing were used to assess human lymphocyte maintenance, receptor repertoire diversity, class switching, and antigen-specific responses following immunization with peptide antigens. Sustained human B cell maintenance correlated with defined supraphysiological ranges of plasma hIL-4 concentrations. T and B cell receptor repertoire analyses demonstrated stable clonal diversity for one month after engraftment, followed by contraction by three months. Immunoglobulin repertoire profiling revealed IL-4–dependent class switching to IgG, with early predominance of IgG3 that declined over time and a gradual increase in IgG1, though subclass distribution varied among donors. Immunization induced antigen-reactive IgG, although many clones displayed low-affinity or cross-reactive binding, consistent with limited affinity maturation. Histological examination revealed tertiary lymphoid structure–like accumulations of human B and T cells within the spleen, without fully developed germinal centers. These findings demonstrate that human IL-4 expression in NOG-hIL-4-Tg mice supports human B cell survival, class switching, and partial IgG maturation, providing a relevant platform for studying human humoral immunity and evaluating antibody-based immunotherapies.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / Animals / Antibodies / antibody / Antigens / B-Lymphocytes - immunology / Cancer / Cell survival / Cells / class switch / Class switching / Cloning / COVID-19 vaccines / Cytokines / Flow cytometry / Germinal centers / Graft versus host disease / humanized mouse / Humans / Humoral immunity / Immune response / Immune system / Immunity (Disease) / Immunoglobulin Class Switching / Immunoglobulin G / Immunoglobulin G - biosynthesis / Immunoglobulin G - immunology / Immunoglobulins / Immunotherapy / Infectious diseases / Interleukin 4 / Interleukin-4 - genetics / Interleukin-4 - immunology / Interleukin-4 - metabolism / Laboratory animals / Leukocytes (mononuclear) / Leukocytes, Mononuclear - immunology / Leukocytes, Mononuclear - metabolism / Lymphocytes / Lymphocytes T / Mice / Mice, Transgenic / Next-generation sequencing / Original Research / Pathogens / Peptides / Peripheral blood mononuclear cells / Plasma / repertoire / Side effects / Spleen / T cell receptor / Transgenic mice