Potential Pitfalls of the Humanized Mice in Modeling Sepsis.

Krzysztof Laudanski,Michael Stentz,Arpit Patel,Matthew Dimeglio,William Furey,Toby Steinberg

doi:10.1155/2018/6563454

Abstract

Humanized mice are a state-of-the-art tool used to study several diseases, helping to close the gap between mice and human immunology. This review focuses on the potential obstacles in the analysis of immune system performance between humans and humanized mice in the context of severe acute inflammation as seen in sepsis or other critical care illnesses. The extent to which the reconstituted human immune system in mice adequately compares to the performance of the human immune system in human hosts is still an evolving question. Although certain viral and protozoan infections can be replicated in humanized mice, whether a highly complex and dynamic systemic inflammation like sepsis can be accurately represented by current humanized mouse models in a clinically translatable manner is unclear. Humanized mice are xenotransplant animals in the most general terms. Several organs (e.g., bone marrow mesenchymal cells, endothelium) cannot interact with the grafted human leukocytes effectively due to species specificity. Also the interaction between mice gut flora and the human immune system may be paradoxical. Often, grafting is performed utilizing an identical batch of stem cells in highly inbred animals which fails to account for human heterogeneity. Limiting factors include the substantial cost and restricting supply of animals. Finally, humanized mice offer an opportunity to gain knowledge of human-like conditions, requiring careful data interpretation just as in nonhumanized animals.

Highlights

Animal models are frequently employed as a precursor to clinical trials and even more broadly in research investigations
The introduction of human stem cell factor, granulocyte macrophage stimulating factor, and IL-3 into the BLT model resulted in more efficient maturation and optimized immunoglobulin production at baseline and after viral infection [38]
Altering the cytokine environment was another way to improve the presence of antigen presenting cells (APCs) like dendritic cells (DCs) [33, 54, 65,66,67]

Summary

Introduction

Animal models are frequently employed as a precursor to clinical trials and even more broadly in research investigations. The development of nonobese diabetic- (NOD-) scid mice further improved the engraftment in comparison to previous immunodeficient host types [17] The success of this subsequent model was attributed to its decreased NK cell activity and the emergence of additional defects of innate immunity, which allowed for higher levels of engraftment [10, 18]. Nanoparticles, plasmids, and lentiviruses were tried to boost the supportive environment of mice bone marrow since optimal cytokine environment is pivotal for the emergence of a complete immune system [21, 38, 39] Despite these efforts and several other modifications, the development of most specialized cells was hampered [40, 41]. Reconstitution of the immune system was found to be more efficient and better tolerated in newborn versus adult mice especially if augmented by the injection of human grafting factors [12]

The Performance of Immune System Components in Humanized Mice

Current Studies of Humanized Mice and Sepsis

Limitations of Humanized Mice Models to Study Sepsis

Conclusions