Abstract
Sepsis remains a major challenge in translational research given its heterogeneous pathophysiology and the lack of specific therapeutics. The use of humanized mouse chimeras with transplanted human hematopoietic cells may improve the clinical relevance of pre-clinical studies. However, knowledge of the human immuno-inflammatory response during sepsis in humanized mice is scarce; it is unclear how similar or divergent mouse and human-origin immuno-inflammatory responses in sepsis are. In this study, we evaluated the early outcome-dependent immuno-inflammatory response in humanized mice generated in the NSG strain after cecal ligation and puncture (CLP) sepsis. Mice were observed for 32 h post-CLP and were assigned to either predicted-to-die (P-DIE) or predicted-to-survive (P-SUR) groups for retrospective comparisons. Blood samples were collected at baseline, 6 and 24 h, whereas the bone marrow and spleen were collected between 24 and 32 h post-CLP. In comparison to P-SUR, P-DIE humanized mice had a 3-fold higher frequency of human splenic monocytes and their CD80 expression was reduced by 1.3-fold; there was no difference in the HLA-DR expression. Similarly, the expression of CD80 on the bone marrow monocytes from P-DIE mice was decreased by 32% (p < 0.05). Sepsis induced a generalized up-regulation of both human and murine plasma cytokines (TNFα, IL-6, IL-10, IL-8/KC, MCP-1); it was additionally aggravated in P-DIE vs. P-SUR. Human cytokines were strongly overridden by the murine ones (approx. ratio 1:9) but human TNFα was 7-fold higher than mouse TNFα. Interestingly, transplantation of human cells did not influence murine cytokine response in NSG mice, but humanized NSG mice were more susceptible to sepsis in comparison with NSG mice (79 vs. 33% mortality; p < 0.05). In conclusion, our results show that humanized mice reflect selected aspects of human immune responses in sepsis and therefore may be a feasible alternative in preclinical immunotherapy modeling.
Highlights
In more than 30 years of intensive research no new specific therapeutics for sepsis have been introduced into clinical care [1]
The more divergent variability is advantageous given that our study focused on the outcome-based differences and not a cecal ligation and puncture (CLP) phenotype produced by a specific needle size
We evaluated the geometric median fluorescence (GMF) of anti-HLA-DR and anti-hCD80 antibodies on human monocytes (Figures 2B,C)
Summary
In more than 30 years of intensive research no new specific therapeutics for sepsis have been introduced into clinical care [1]. The failure of anti-sepsis therapeutics to modulate the host response has been attributed to a large part to flawed preclinical studies [5,6,7]. One of the most commonly used mouse strains for humanization is the NSG (NOD scid gamma) strain [11]; NSG mice have composite immunodeficiency given that they lack lymphocytes, NK cells, and macrophages and have an impaired complement system, enabling an efficient engraftment of the human cells with a relatively low risk of developing graft-vs.-host disease
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