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    A Novel Mouse Model for Stable Engraftment of a Human Immune System and Human Hepatocytes

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    Author
    Strick-Marchand, H; Dusseaux, M; Darche, S; Huntington, ND; Legrand, N; Masse-Ranson, G; Corcuff, E; Ahodantin, J; Weijer, K; Spits, H; ...
    Date
    2015-03-17
    Source Title
    PLoS One
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Huntington, Nicholas
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Strick-Marchand, H., Dusseaux, M., Darche, S., Huntington, N. D., Legrand, N., Masse-Ranson, G., Corcuff, E., Ahodantin, J., Weijer, K., Spits, H., Kremsdorf, D. & Di Santo, J. P. (2015). A Novel Mouse Model for Stable Engraftment of a Human Immune System and Human Hepatocytes. PLOS ONE, 10 (3), https://doi.org/10.1371/journal.pone.0119820.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257690
    DOI
    10.1371/journal.pone.0119820
    Abstract
    Hepatic infections by hepatitis B virus (HBV), hepatitis C virus (HCV) and Plasmodium parasites leading to acute or chronic diseases constitute a global health challenge. The species tropism of these hepatotropic pathogens is restricted to chimpanzees and humans, thus model systems to study their pathological mechanisms are severely limited. Although these pathogens infect hepatocytes, disease pathology is intimately related to the degree and quality of the immune response. As a first step to decipher the immune response to infected hepatocytes, we developed an animal model harboring both a human immune system (HIS) and human hepatocytes (HUHEP) in BALB/c Rag2-/- IL-2Rγc-/- NOD.sirpa uPAtg/tg mice. The extent and kinetics of human hepatocyte engraftment were similar between HUHEP and HIS-HUHEP mice. Transplanted human hepatocytes were polarized and mature in vivo, resulting in 20-50% liver chimerism in these models. Human myeloid and lymphoid cell lineages developed at similar frequencies in HIS and HIS-HUHEP mice, and splenic and hepatic compartments were humanized with mature B cells, NK cells and naïve T cells, as well as monocytes and dendritic cells. Taken together, these results demonstrate that HIS-HUHEP mice can be stably (> 5 months) and robustly engrafted with a humanized immune system and chimeric human liver. This novel HIS-HUHEP model provides a platform to investigate human immune responses against hepatotropic pathogens and to test novel drug strategies or vaccine candidates.

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