HUMAN CD4 AND HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II (DQ6) TRANSGENIC MICE - SUPERSENSITIVITY TO SUPERANTIGEN-INDUCED SEPTIC SHOCK

Rodents are significantly less sensitive to enterotoxin-induced shock, and are thus not valid human disease models. Here, we describe a mous e strain carrying the human CD4 and human major histocompatibility com plex (MHC) class II (DQ6) transgenes in an endogenous CD4- and CD8-def icient background. T lymphocytes from these animals react to minute am ounts (10-100 times less than control mice) of staphylococcal enteroto xin B (SEB) in vitro, similar to concentrations to which human cells r eact. In vivo, these double-transgenic, double-knockout mice succumb t o 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, tum or 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 C D4 and MHC class II molecules can render mice supersensitive to supera ntigen-induced septic shock syndrome. This animal model mimics the pro gression of septic shock in man by transforming normally resistant mic e into hypersensitive SEB responders, a trait that is characteristic o f humans. Mice that have been humanized by exchanging autochthonous su perantigen ligands by their human equivalents may be useful to deciphe r superantigen responses in vivo and to assess the pathogenesis of sup erantigen-associated diseases.