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      Humanized Mice as Unique Tools for Human-Specific Studies

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          Abstract

          With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use.

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          Most cited references156

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          Of mice and not men: differences between mouse and human immunology.

          Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
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            Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

            The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.
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              Humanized mice for immune system investigation: progress, promise and challenges.

              Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of 'humanized' mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, we discuss recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.
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                Author and article information

                Contributors
                qchen@imcb.a-star.edu.sg
                Journal
                Arch Immunol Ther Exp (Warsz)
                Arch. Immunol. Ther. Exp. (Warsz.)
                Archivum Immunologiae et Therapiae Experimentalis
                Springer International Publishing (Cham )
                0004-069X
                1661-4917
                7 February 2018
                7 February 2018
                2018
                : 66
                : 4
                : 245-266
                Affiliations
                [1 ]GRID grid.418812.6, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), ; Proteos, 61 Biopolis Drive, Singapore, 138673 Singapore
                [2 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Biochemistry, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, 117596 Singapore
                [3 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, 117545 Singapore
                [4 ]ISNI 0000 0004 1758 4591, GRID grid.417009.b, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, ; Guangzhou, 510150 China
                Article
                506
                10.1007/s00005-018-0506-x
                6061174
                29411049
                3840044e-5c30-4b62-a0db-6eb169f3497c
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 15 August 2017
                : 4 January 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001381, National Research Foundation Singapore;
                Award ID: NRF-NRFF2017-03
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001349, National Medical Research Council;
                Award ID: NMRC/TCR/014-NUHS/2015
                Funded by: FundRef http://dx.doi.org/10.13039/501100001348, Agency for Science, Technology and Research;
                Award ID: A*STAR graduate scholarship
                Award Recipient :
                Categories
                Review
                Custom metadata
                © L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2018

                Immunology
                humanized mice,human specificity,precision therapy,human diseases,drug testing
                Immunology
                humanized mice, human specificity, precision therapy, human diseases, drug testing

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