A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production

Blood. 2017 Feb 23;129(8):959-969. doi: 10.1182/blood-2016-04-709584. Epub 2017 Jan 11.

Abstract

Humanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human interleukin 6 (IL-6) gene encoding the cytokine that is important for B- and T-cell differentiation was knocked into its respective mouse locus. The provision of human IL-6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum immunoglobulin G (IgG). In addition, immunization with ovalbumin (OVA) induced OVA-specific B cells only in human IL-6 knock-in mice. These OVA-specific antibodies displayed the highest frequency of somatic mutation, further suggesting that human IL-6 is important for efficient B-cell activation and selection. We conclude that human IL-6 knock-in mice represent a novel and improved model for human adaptive immunity without relying on complex surgery to transplant human fetal thymus and liver. These mice can therefore be used to exploit or evaluate immunization regimes that would be unethical or untenable in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Antibody Formation*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • Chickens
  • Gene Expression
  • Gene Knock-In Techniques* / methods
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / immunology
  • Humans
  • Immunization
  • Immunoglobulin Class Switching*
  • Immunoglobulin G / immunology
  • Interleukin-6 / genetics*
  • Interleukin-6 / immunology
  • Mice
  • Ovalbumin / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology

Substances

  • IL6 protein, human
  • Immunoglobulin G
  • Interleukin-6
  • Ovalbumin