Human CD4 and human major histocompatibility complex class II (DQ6) transgenic mice: supersensitivity to superantigen‐induced septic shock

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.

Superantigens Subvert the Neutrophil Response To Promote Abscess Formation and Enhance Staphylococcus aureus SurvivalIn Vivo

“…A general feature of most bacterial SAgs is that these toxins do not efficiently bind mouse MHC-II molecules (46,47). S. aureus Newman encodes the SEA SAg (48), so we first tested the ability of recombinant SEA protein to activate splenocytes isolated from both B6 and DR4-B6 transgenic mice.…”

Comparative Analysis of Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Activity in Serum and Lethality in Mice and Rabbits Pretreated with the Staphylococcal Superantigen Toxic Shock Syndrome Toxin 1

“…Murine resistance to shock induced by staphylococcal or streptococcal superantigens may likewise be due to a relative impairment in the ability of these toxins to induce cytokine release from murine immune cells. Transgenic mice expressing human CD14 or HLA-DQ6 exhibited significant increases in susceptibility to LPS or staphylococcal enterotoxin B (8,23), respectively, thereby linking species variability in LPS or superantigen sensitivity to minor species differences in the cellular receptors for these toxins.…”

HLA-DQ6 and ingestion of contaminated water: possible gene–environment interaction in an outbreak of Leptospirosis

“…49 Staphylococcal superantigen (SEB) also shows increased toxicity in transgenic mice expressing an HLA-DQ6 allele with human CD4. 50 Leptospiral superantigens have not yet been described. However, our model can be tested by evaluating cases of leptospirosis for the expanded T-cell receptor V bchain usage often seen during levels of superantigenmediated disease.…”