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Human CD4 and human major histocompatibility complex class II (DQ6) transgenic mice: supersensitivity to
R S Yeung1, J M Penninger, T Kündig
1Amgen Research Institute, Toronto, Canada.
Abstract:
Rodents are significantly less sensitive to enterotoxin-induced shock, and are thus not valid human disease models. Here, we describe a mouse strain carrying the human CD4 and human major histocompatibility complex (MHC) class II (DQ6) transgenes in an endogenous CD4- and CD8-deficient background. T lymphocytes from these animals react to minute amounts (10-100 times less than control mice) of staphylococcal enterotoxin B (SEB) in vitro, similar to concentrations to which human cells react. In vivo, these double-transgenic, double-knockout mice succumb to normally sublethal amounts of SEB. This sensitivity is not due to a biased T cell receptor V beta repertoire, increased T cell reactivity, or increased sensitivity to macrophage-derived cytokines. Rather, tumor necrosis factor (TNF)-alpha production by T cells and serum levels of TNF-alpha correlate precisely with the clinical syndrome, showing a biphasic T cell-dependent response. These data show that both human CD4 and MHC class II molecules can render mice supersensitive to superantigen-induced septic shock syndrome. This animal model mimics the progression of septic shock in man by transforming normally resistant mice into hypersensitive SEB responders, a trait that is characteristic of humans. Mice that have been humanized by exchanging autochthonous superantigen ligands by their human equivalents may be useful to decipher superantigen responses in vivo and to assess the pathogenesis of superantigen-associated diseases.
Insights
Mice engineered with human CD4 and MHC class II genes exhibit human-like sensitivity to staphylococcal enterotoxin B (SEB), creating a valuable model for studying superantigen-induced septic shock.
Area of Science:
- Immunology
- Genetics
- Pathology
Background:
- Rodents exhibit lower sensitivity to enterotoxin-induced shock, limiting their utility as human disease models.
- Understanding superantigen responses is crucial for deciphering diseases like toxic shock syndrome.
Purpose of the Study:
- To develop a mouse model that accurately mimics human sensitivity to superantigen-induced septic shock.
- To investigate the mechanisms underlying superantigen hypersensitivity in a humanized mouse model.
Main Methods:
- Generation of a novel mouse strain with human CD4 and human major histocompatibility complex (MHC) class II (DQ6) transgenes in a CD4/CD8-deficient background.
- In vitro and in vivo assessment of T lymphocyte reactivity to staphylococcal enterotoxin B (SEB).
- Analysis of cytokine production, specifically tumor necrosis factor (TNF)-alpha, and its correlation with disease progression.
Main Results:
- Transgenic mice demonstrated heightened sensitivity to SEB, reacting to significantly lower concentrations compared to control mice.
- In vivo administration of SEB led to septic shock in the humanized mice, mirroring human disease progression.
- Tumor necrosis factor (TNF)-alpha production by T cells and serum levels correlated directly with the severity of the clinical syndrome.
Conclusions:
- Human CD4 and MHC class II molecules can confer hypersensitivity to superantigen-induced septic shock in mice.
- This humanized mouse model effectively replicates human susceptibility to SEB, offering a powerful tool for research.
- The model facilitates the study of superantigen responses in vivo and the pathogenesis of associated diseases.