Immunodeficient BRGSF Mouse Model

Immunodeficient mouse

Compared to traditional immunodeficient strains, such as NOD-SCID and NSG, the BRGSF mouse represents the most immunodeficient model generated to date, with defect of both the murine lymphoid and myeloid compartments, and thus represents a strongly adapted animal model for xenograft of human tumor and/or immune system.

Applications

This next-generation mouse is a unique preclinical model to study:

Tumor xenograft (including CDX, PDX)
- Standard of care therapies (surgery, chemotherapies, radiotherapies, etc.)
- Cell therapies (including NK, CAR-T cell) efficacy and depletion assessment
Human CD34⁺ hematopoietic stem cell engraftment
Human PBMC cell engraftment
Complement-dependent cytotoxicity (CDC) studies

BRGSF features

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Highly immunodeficient (T, B, NK, myeloid cells) due to Rag2, IL-2Rγc and Flk2 KO
Highly permissive to patient-derived xenografts (PDXs) and cell line engraftment by virtue of the SIRPα^NOD expression and reduced murine myeloid compartment
Robustness to radiotherapies, chemotherapies due to BALB/c background and the absence of the SCID mutation
A complete, functional complement system makes this a powerful tool for complement-dependent cytotoxicity (CDC) studies
Stable phenotype throughout lifespan

FAQ on BRGSF mouse models

1. What is the BRGSF mouse model?

The BRGSF is the most immunodeficient mouse model generated to date, with defects in both myeloid and lymphoid compartments (Rag2^-/-, IL 2Rγ^-/-, Flk2^-/-). Here is its genetic background:

BRGSF

2. What makes the BRGSF an immunodeficient mouse model?

The BRGSF carries multiple genetic defects, including mutations in:

The recombination-activating gene 2 (RAG2). Together with RAG1, RAG2 initiates the VDJ recombination, a site-specific recombination process that ensures the generation of a large repertoire of unique antigen receptors on B and T lymphocytes. As such, mutations in RAG2 cause depletion in these immune cells.
The gamma chain of the interleukin 2 receptor (IL-2Rγc). The gamma chain is an essential subunit of functional IL-2 receptors, as well as four other interleukins (IL-4, IL-7, IL-9, and IL-15). Mutations in this gene lead to X-linked severe combined immune deficiency (X-SCID), a combined cellular and humoral immunodeficiency characterized by a profound T- and NK-cell deficiency.
The fetal liver kinase-2 (Flk2). This is a receptor tyrosine kinase that regulates the development of the myeloid compartment; as such, mutations in Flk2 lead to a strongly reduced myeloid cell compartment.

3. How would you make the most of the BRGSF?

The BRGSF mouse model represents a valuable tool for:

Human hematopoietic cell engraftment
Tumor engraftment
Efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy
Myeloid compartment development studies

4. Which unique valuable features do BRGSF mice possess?

BALB/c genetic background

As such, these animals represent valuable tools to predict clinical response to certain anticancer drugs, and for long-term transplantation studies. Indeed, contrary to NOD and NOD-derived strains such as NSG and NOG, BRSGF mice do not carry the Prkdc mutation and, therefore, do not show the SCID side effect of high sensitivity to radiation, T-cell leakage, and increased incidence of thymic lymphoma formation.

NOD-specific polymorphic SIRPα

This renders BRGSF mice highly permissive to human cell engraftment. SIRPα is a transmembrane glycoprotein expressed on early hematopoietic progenitors, on myeloid cells such as macrophages and granulocytes, and on dendritic cells and neurons. It binds CD47, an immunoglobulin that acts as a self-marker for macrophages. Importantly, several studies have shown that Cd47^−/− mouse hematopoietic cells grafted into wild-type mice, and into mice lacking T, B and NK cells, are rapidly ‘eaten’ by macrophages, as are wild-type cells if the CD47–SIRPα binding is disrupted. Polymorphisms in SIRPα thereby represent a potent genetic determinant of human hematopoietic stem cell engraftment and host survival.

Fully functional complement cascade

Unlike NOG-based strains, where C5A is knockout, BRGSF mice possess a fully functional complement cascade.

5. How do BRGSF mice compare to other immunocompromised mice?

brgsf-nsg

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References for model validation

Model validation

Lopez-Lastra S, Masse-Ranson G, Fiquet O, Darche S, Serafini N, Li Y, Dusséaux M, Strick-Marchand H, Di Santo JP. A functional DC cross talk promotes human ILC homeostasis in humanized mice. Blood Adv. 2017 Apr 6.

Li Y, Mention JJ, Court N, Masse-Ranson G, Toubert A, Spits H, Legrand N, Corcuff E, Strick-Marchand H, Di Santo JP. A novel Flt3-deficient HIS mouse model with selective enhancement of human DC development. Eur J Immunol. 2016 May.

Legrand N1, Huntington ND, Nagasawa M, Bakker AQ, Schotte R, Strick-Marchand H, de Geus SJ, Pouw SM, Böhne M, Voordouw A, Weijer K, Di Santo JP, Spits H. Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proc Natl Acad Sci U S A. 2011 Aug 9.

Case studies

Vaccine development:
Fior J. SupT1 Cell Infusion as a Possible Cell-Based Therapy for HIV: Results from a Pilot Study in Hu-PBMC BRGS Mice. Vaccines (Basel). 2016 Apr 26.

Cell therapy:
Valton J, Guyot V, Boldajipour B, Sommer C, Pertel T, Juillerat A, Duclert A, Sasu BJ, Duchateau P, Poirot L. A Versatile Safeguard for Chimeric Antigen Receptor T-Cell Immunotherapies. Sci Rep. 2018 Jun 12

John P Veluchamy, Silvia Lopez-Lastra, Jan Spanholtz, Fenna Bohme, Nina Kok, Daniëlle A M Heideman, Henk M W Verheul, James P Di Santo Tanja D de Gruijl, Hans J van der Vliet. In Vivo Efficacy of Umbilical Cord Blood Stem Cell-Derived NK Cells in the Treatment of Metastatic Colorectal Cancer. Front Immunol . 2017 Feb 6.

Patent

Di Santo JP and Mention JJ. Dentritic cell-boosted humanized immune system mice. PCT/US/2010/029800. WO 2010/115115 A1. Patent 2010.