Sepsis-induced human lymphocyte apoptosis and cytokine production in humanized mice

Sepsis is the leading cause of death in critically ill patients in the United States with over 210,000 deaths annually. One stumbling block to an effective therapy of sepsis has been the lack of a clinically relevant animal model. There are important distinctions in the mouse versus human immune system regarding the host response to invading pathogens. These differences may explain the disappointing results in many sepsis clinical trials despite the clear efficacy of these agents in mouse models of sepsis. The purpose of the present study was to develop a humanized mouse model of sepsis and to determine if the model recapitulated the major findings of lymphocyte apoptosis and cytokine response that exist in patients with sepsis. Two-day-old NOD-scid IL2r gamma(null) mice received an adoptive transfer of hCD34(+) hematopoietic cord blood stem cells. These mice acquired a functional human innate and adaptive immune system, as evidenced by the development of all lineages of human immune cells as well as by mounting a DTH response. Eight weeks post-transfer, mice were made septic using the highly clinical relevant CLP model of sepsis, and sepsis induced marked elevations in human pro-and anti-inflammatory cytokines as well as a dramatic increase in human T and B cell apoptosis. Collectively, these results show that the humanized mouse model recapitulates many of the classic findings in patients with sepsis. Therefore, it represents an advanced, clinically relevant model for mechanistic studies of sepsis and testing of novel therapies. J. Leukoc. Biol. 86: 219-227; 2009.