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Animal models play a crucial role in the pre-clinical anti-tumor drug evaluation system. However, the current common animal models cannot truely simulate the tumor microenvironment (TME) of patient with cancer, especially has great limitations in the translational research of immunotherapy. Therefore, there is an urgent to establish animal models with the human immune system for relevant translational research. Mouse models engrafted with human immune systems refers to models in which human hematopoietic cells (HSCs), lymphocytes or tissues are implanted in immunodeficient mice to make them have human immune functions. This model can be used to study the growth of tumors in the environment of the human immune system, and for the evaluation of anti-tumor therapy, especially the efficacy of immunotherapy and related mechanisms.

Construction Strategy:

The CD34+ cells were isolated from fetal liver (FL) or umbilical cord blood (UCB) using human D34 immunomagnetic beads (Miltenyi Biotec). Newborn mice were irradiated with a sublethal dose, and then CD34+ haematopoietic stem cells (HSCs) was injected into the liver of the mice. All mouse operations are performed under sterile conditions of laminar flow.

Strain Description:

  •    The BRGSF-HIS mouse possesses the most functional reconstituted human immune system currently available on the market. Indeed, this mouse provides a very practical and reliable research platform for evaluating targeted biological drugs related to the regulation of human immune function.
  •    The BRGSF-HIS mouse model possesses all of the major human hematopoietic cell subsets, such as B cells, T cells (including CD4+ CD8+Treg cells), NK cells, and the myeloid compartment including classical dendritic cells (cDCs), plasmacytoid cells (pDCs) and monocytes/macrophages.
  •    No symptoms of sepsis - macrophages differentiated from human hematopoietic stem cells (HSCs) will not engulf mouse red blood cells (RBCs).
  •    Highly permissive to patient-derived xenografts (PDXs) and cell line engraftments (CDXs) by virtue of the SIRPαNOD allele expression.
  •    Suitable to assess the effects of radiation treatment in vivo due to the absence of the SCIDPrkdc mutation on a BALB/c background.
  •    A powerful tool for complement-dependent cytotoxicity (CDC) studies because of the presence of a functional murine complement system

Research & Applications

The BRGSF-HIS mouse model can address a broad spectrum of therapeutic areas and applications, including:

  •   Antibody Drugs: the combinations of therapeutic polyclonal or monoclonal antibodies, such as, in vivo activation of NK and T cells to suppress tumor growth in tumor engrafted mice.
  •   Immuno-oncology (e.g., blood cancer, solid tumor)
  •   Autoimmune diseases (e.g., systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic vasculitis, autoimmune hemolytic anemia, etc.)
  •   Infectiology (e.g., HIV, dengue virus, Ebola virus, CMV, RSV, HTLV, EBV)
  •   Vaccine and drug screening (e.g., chimeric antigen receptor (CAR) T cell therapy, evaluation of therapeutic antibodies)
  •   Personalized medicine (e.g., prediction of individual response to different therapies)

Phenotype Validation:

Figure 1. Distribution of human myeloid subsets in BRGSF mice and effect of Flt3L on their development. Representative flow cytometry immunophenotypic analysis of hCD45+HLA−DR+CD19CD3CD56 cells from bone marrow (A) and spleen (C) of an Flt3L-treated mouse and a PBS-treated littermate engrafted with the same CD34+ HSC donor in BRGSF mice.

Selected References:

1. Simpson, J. A.; Brown, M. E. Making HIS Mice More Human‐like. J. Leukoc. Biol. 2020, 107 (1), 9–10.

2. Lopez-Lastra, S.; Masse-Ranson, G.; Fiquet, O.; Darche, S.; Serafini, N.; Li, Y.; Dusséaux, M.; Strick-Marchand, H.; Di Santo, J. P. A Functional DC Cross Talk Promotes Human ILC Homeostasis in Humanized Mice. Blood Adv. 2017, 1 (10), 601–614.

3. Li, Y.; Mention, J.-J.; Court, N.; Masse-Ranson, G.; Toubert, A.; Spits, H.; Legrand, N.; Corcuff, E.; Strick-Marchand, H.; Di Santo, J. P. A Novel Flt3-Deficient HIS Mouse Model with Selective Enhancement of Human DC Development. Eur. J. Immunol. 2016, 46 (5), 1291–1299.

4. Legrand, N.; Huntington, N. D.; Nagasawa, M.; Bakker, A. Q.; Schotte, R.; Strick-Marchand, H.; de Geus, S. J.; Pouw, S. M.; Böhne, M.; Voordouw, A.; et al. Functional CD47/Signal Regulatory Protein Alpha (SIRPα) Interaction Is Required for Optimal Human T- and Natural Killer- (NK) Cell Homeostasis in Vivo. Proc. Natl. Acad. Sci. 2011, 108 (32), 13224–13229.

5. Valton J, Guyot V, Boldajipour B, et al. A Versatile Safeguard for Chimeric Antigen Receptor T-Cell Immunotherapies. Scientific Reports, 2018, 8(1).

In 2020, Cyagen reached a strategic partnership with genOway. Founded in 1999, genOway is a leading international supplier of laboratory mice for preclinical scientific research. Cyagen is excited to introduce BRGSF mice as a featured product line that represents the most adapted animal model to study and predict human immune responses in vivo. See why we recommend genOway's BRGS™ mouse model:

1.  Robust verification by both Industry leaders and literatures: Services and products from genOway have been cited many times in high-impact academic journals such as Cell, Nature, Science, and PNAS. As a partner of the the EU Research and Innovation programme (Horizon 2020), its immune checkpoint (ICP) and severe combined immunodeficient (SCID) model series have been jointly verified by the company and its partners worldwide, including leaders in the fields of immuno-oncology and immunotherapy, large pharmaceutical companies, biotechnology companies, research institutions, and more.

2.  Leading supplier of genetically engineered animal models in Europe and the United States: genOway has obtained patent licenses for all its technologies used to construct models, and is the only supplier that can guarantee you the opportunity to operate all the models on your own. Founded in 1999, genOway has 21 years of experience in animal model services, the company now has developed into a leader in the field of customized, genetically modified (GM) mouse, rat, and cell model creation, while serving international pharmaceuticals (Novartis, Pfizer, BMS, Janssen, and more.) and world-famous academic research centers (National Institutes of Health (NIH), Institut Pasteur, etc.) with their services.

3.  Comprehensive Intellectual Property (IP) Protection: Clear and independent IP rights are an essential facet of successful drug discovery projects. genOway provides various disease animal models with a wide range of patents and license agreements to ensure that the IP rights of the model are clear. This guarantees you freedom to operate (FTO) along with the provisions of the model.

4.  Specific Model Genetic Background: All models are provided on a specific genetic strain background, of accurate and traceable sources, and includes periodic genetic testing performed in colony maintenance to ensure the reproducibility of your research results.

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