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The overall objective is to establish the third generation humanized mouse models for infection and cancer research within our LKS faculty of medicine. 

The platform technology involves the development of the third generation humanized mouse models using immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice that we imported from the US Jackson Laboratory (Bar Harbor, ME) after two years of efforts.  With the help of HKU Laboratory Animal Unit, a breeding colony of NSG mice has been successfully established, which allows further development of the proposed platform. 

During our preliminary studies, we have already established the NSGhuPBL mouse model using human peripheral blood mononuclear cells (PBMC) for HIV/AIDS research, based on our experimental protocols approved by the Committee on the Use of Live Animals in Teaching and Research (CULATR).  Taking one step forward, we aim to expand the application of the NSGhuPBL mouse model for human cancer research and to use human cord-blood stem cells to establish the NSGhuCBS mouse model for infection and various cancers during the proposed funding period.  Since the NSGhuCBS mouse model bears a more complete human immune system, it will allow the functional analysis of diverse human immune cells in the context of different infections and cancers in a more comprehensive way, and therefore, will eventually promote the high quality research and publications. 






Significance of the Platform Technology
(1) There are many unsolved biomedical problems due to the lack of a proper animal model. For example, during HIV-1 infection, how are latently infected cells distributed in the body? During our preliminary studies, we found that the NSGhuPBL mouse model displays rapid and sufficient reconstitution of human T lymphocytes in multiple tissue/organ compartments.  Critically, the NSGhuPBL mouse model supports live HIV-1 infection for pathogenesis and immune interventions studies, which has already resulted in two scientific publications including one in Nature Microbiology and the third paper is under revision in Journal of Clinical Investigation. Furthermore, in collaboration with our co-PIs of this proposal, we recently found that the NSGhuPBL mouse model supports well the growth of various human cancer cells including mesothelioma, hepatocellular carcinoma and esophageal squamous cell carcinoma, which not only expands its application for cancer immunology research but also allows the testing of various anti-tumor interventions in the context of human T cells. 
(2) As for potential impact from the proposed Platform Technology, since the proposed NSGhuCBS model allows the reconstitution of human B cell, monocyte/macrophage and dendritic cells in addition to T lymphocytes in multiple tissue/organ compartments, the establishment of this model will further expand our capacity of humanized mouse models for infection and cancer research.  For example, this model will allow us to investigate different types of latently HIV-infected immune cells throughout the body in addition to CD4+ T cells.  Similar advantages will apply to other infections (e.g. influenza infection in lungs) and various cancer research projects within our faculty with great potential impact in generating more high impact scientific publications and new immunotherapeutic products for improving human health. 


Uniqueness of the Platform Technology
The proposed Platform Technology is unique in that the third generation immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice is very different from other humanized mouse models such as the conventional severe combined immunodeficiency (SCID) mice. NSG mice carry two mutations including a SCID mutation and a complete null allele of the IL2 receptor common gamma chain (IL2rgnull). The SCID mutation in the DNA repair complex protein Prkdc renders the mice B and T cell deficient. The IL2rgnull mutation prevents cytokine signaling through multiple receptors, leading to a deficiency in functional NK cells. Therefore, NSG mice allow to be humanized by engraftment of human CD34+ hematopoietic stem cells (HSC), PBMC, patient derived xenografts (PDX), or adult stem cells and tissues.  Functionally, the conventional SCID mice do not allow the population of human T cells into different tissues or organs, which limits its human relevance.  Moreover, the conventional SCID mice only support transient HIV-1 infection after humanization, which does not model the natural course of patients’ persistent infections.  Similarly, since cancer is also a chronic disease, it is necessary to investigate the long-term interaction of human immune cells with cancer microenvironment, which cannot be done in the conventionally humanized SCID mice.  The uniqueness of NSG mice enables biomedical research in human immune function, infectious disease, diabetes, oncology, and stem cell biology.  Therefore, through the testing of various immune interventions in the NSG-based NSGhuPBL and NSGhuCBS mouse models, we aim to discover new vaccine, antibody, CAR-T or small molecule drugs that may solve significant health problems in society besides pathogenesis and tumorigenesis studies.  Hopefully, some of the vaccine, antibody, CAR-T or small molecule drugs will be developed by industry partners to benefit patients in Hong Kong and other part of the world.  



Our Publications

(1) Wu X, Liu L, Cheung KW, Wang H, Lu X, Cheung AK, Liu W, Huang X, Li Y, Chen ZW, Chen SM, Zhang T, Wu H, Chen Z*. Brain Invasion by CD4(+) T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice. J Neuroimmune Pharmacol. 2016 Sep;11(3):572-83.


(2) Cheung AKL, Kwok HY, Huang Y, Chen M, Mo Y, Wu X, Lam KS, Kong HK, Lau TCK, Zhou J, Li J, Cheng L, Kiat Lee B, Peng Q, Lu X, An M, Wang H, Shang H, Zhou B, Wu H, Xu A, Yuen KY, Chen Z*. Gut-homing Δ42PD1+Vδ2 T cells promote innate mucosal damage via TLR4 during acute HIV type 1 infection. Nat Microbiol. 2017 Oct;2(10):1389-1402.


(3)  Wu X, Guo J, Niu M, An M, Liu L, Wang H, Jin X, Zhang Q, Lam KS, Wu T, Wang H, Wang Q, Du Y, Li J, Cheng L, Tang HY, Shang H, Zhang L, Zhou P, Chen Z*. Tandem bispecific neutralizing antibody eliminates HIV-1 infection in humanized mice. Journal of Clinical Investigation. 2018 Apr 23. pii: 96764. doi: 10.1172/JCI96764.


(4) Ling L, Tang X, Huang X, Li J, Wang H, Chen Z. AAV-Vectored Fms-Related Tyrosine Kinase 3 Ligand Inhibits CD34+ Progenitor Cell Engraftment in Humanized Mice. J Neuroimmune Pharmacol. 2018 Dec;13(4):541-550. doi: 10.1007/s11481-018-9819-0. Epub 2018 Oct 30.


(5) Ling L, Wu T, To KKW, Cheung KW, Lui KOL, Niu M, Lam KS, Wang CC, Li J, Wang H, Yuen KY, Chen Z. Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice. 2019 Mar 15;33(4):F1-F12. doi: 10.1097/QAD.0000000000002149.