NSG mouse
NSG, or NOD scid gamma (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ), is a strain of inbred laboratory mice, among the most immunodeficient described to date.[1] NSG mice lack mature T cells, B cells, and natural killer (NK) cells.[2] NSG mice are also deficient in multiple cytokine signaling pathways, and they have many defects in innate immunity.[2][3] The compound immunodeficiencies in NSG mice permit the engraftment of a wide range of primary human cells, and enable sophisticated modeling of many areas of human biology and disease. NSG mice were developed in the laboratory of Dr. Leonard Shultz at The Jackson Laboratory.
Features of NSG mice
- The genetic background, derived from inbred NOD mouse strain NOD/ShiLtJ, contributes reductions in innate immunity that include an absent hemolytic complement system, reduced dendritic cell function, and defective macrophage activity.[3] The NOD/ShiLtJ background also contributes an allele of the Sirpa gene that renders the bone marrow niche very permissive to colonization by human hematopoietic stem cells.[4]
- The Prkdcscid mutationa, commonly known as “scid” or “severe combined immunodeficiency”, essentially eliminates adaptive immunity.[5] Prkdcscid is a loss-of-function mutation in the mouse homologue of the human PRKDC gene, which encodes a protein that resolves DNA strand breaks that occur during V(D)J recombination in developing T and B lymphocytes.[6] Mice homozygous for the mutation have severely reduced numbers of mature T and B cells.[3][5] The phenotypic penetrance of Prkdcscid varies among inbred strain backgrounds, but the mutation is most effective at eliminating adaptive immunity on the NOD genetic background.[3]
- The Il2rgtm1Wjl targeted mutationb is a complete null mutation in the gene encoding the interleukin 2 receptor gamma chain (IL2Rγ, homologous to IL2RG in humans).[7] IL2Rγ is a common component of the cell surface receptors that bind and transduce signals from six distinct interleukins. Signaling through IL2Rγ is required for the differentiation and function of many hematopoietic cells.[7] Notably, the absence of IL2Rγ blocks NK cell differentiation, and thereby removes a major obstacle preventing the efficient engraftment of primary human cells.[2][5]
Research applications of NSG include
- Primary human lung tumor xenografts that preserve the tumor microenvironment during long-term engraftment [8]
- Humanized model for evaluation of possible cancer curing gene therapy. [9]
- Models of acute or chronic leukemia established using cancer cells collected from patients (A complete list of publications is available here)
- A highly sensitive platform for studying epithelial [10] and cancer stem cells [11]
- Establishing a functional, humanized immune system from engrafted human hematopoietic stem cells [12][13] and progenitors [14]
- Humanized models for studying human-specific infectious diseases like HIV,[15] Epstein Barr virus,[16] malaria,[17] and Dengue fever.[18][19] Humanized models also aid in testing new therapies [15]
- Studying allograft rejection after pancreatic islet transplantation therapy for type 1 diabetes [20]
References
- ↑ Shultz LD, Ishikawa F, Greiner DL (2007). "Humanized mice in translational biomedical research". Nat. Rev. Immunol. 7 (2): 118–130. doi:10.1038/nri2017. PMID 17259968.
- ↑ 2.0 2.1 2.2 Shultz LD; Lyons BL; Burzenski LM et al. (2005). "Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells". J. Immunol. 174 (10): 6477–89. doi:10.4049/jimmunol.174.10.6477. PMID 15879151.
- ↑ 3.0 3.1 3.2 3.3 Shultz LD; Schweitzer PA; Christianson SW et al. (1995). "Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice". J. Immunol. 154 (1): 180–91. PMID 7995938.
- ↑ Takenaka K; Prasolava TK; Wang JC et al. (2007). "Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells". Nat. Immunol. 8 (12): 1313–23. doi:10.1038/ni1527. PMID 17982459.
- ↑ 5.0 5.1 5.2 Greiner DL, Hesselton RA, Shultz LD (1998). "SCID mouse models of human stem cell engraftment". Stem Cells 16 (3): 166–177. doi:10.1002/stem.160166. PMID 9617892.
- ↑ Blunt T; Finnie NJ; Taccioli GE et al. (1995). "Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation". Cell 80 (5): 813–23. doi:10.1016/0092-8674(95)90360-7. PMID 7889575.
- ↑ 7.0 7.1 Cao X; Shores EW; Hu-Li J et al. (1995). "Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain". Immunity 2 (3): 223–38. doi:10.1016/1074-7613(95)90047-0. PMID 7697543.
- ↑ Simpson-Abelson MR; Sonnenberg GF; Takita H et al. (2008). "Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice". J. Immunol. 180 (10): 7009–18. doi:10.4049/jimmunol.180.10.7009. PMID 18453623.
- ↑ Escobar G, Moi D, Ranghetti A et al. (Jan 2014). "Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression.". Sci Transl Med. 6 (217): 217. doi:10.1126/scitranslmed.3006353. PMID 24382895.
- ↑ Eirew P; Stingl J; Raouf A et al. (2008). "A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability". Nat. Med. 14 (12): 1384–9. doi:10.1038/nm.1791. PMID 19029987.
- ↑ Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008). "Efficient tumour formation by single human melanoma cells". Nature 456 (7222): 593–598. doi:10.1038/nature07567. PMC 2597380. PMID 19052619.
- ↑ Ishikawa F, Yasukawa M, Lyons B, et al. (2005). "Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice". Blood 106 (5): 1565–73. doi:10.1182/blood-2005-02-0516. PMC 1895228. PMID 15920010.
- ↑ Giassi LJ; Pearson T; Shultz LD et al. (August 2008). "Expanded CD34+ human umbilical cord blood cells generate multiple lymphohematopoietic lineages in NOD-scid IL2rgamma(null) mice". Exp. Biol. Med. (Maywood) 233 (8): 997–1012. doi:10.3181/0802-RM-70. PMC 2757278. PMID 18653783.
- ↑ Majeti R, Park CY, Weissman IL (2007). "Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood". Cell Stem Cell 1 (6): 635–645. doi:10.1016/j.stem.2007.10.001. PMC 2292126. PMID 18371405.
- ↑ 15.0 15.1 Kumar P; Ban HS; Kim SS et al. (2008). "T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice". Cell 134 (4): 577–86. doi:10.1016/j.cell.2008.06.034. PMC 2943428. PMID 18691745.
- ↑ Strowig T; Gurer C; Ploss A et al. (2009). "Priming of protective T cell responses against virus-induced tumors in mice with human immune system components". J. Exp. Med. 206 (6): 1423–34. doi:10.1084/jem.20081720. PMC 2715061. PMID 19487422.
- ↑ Jiménez-Díaz MB; Mulet T; Viera S et al. (2009). "Improved murine model of malaria using Plasmodium falciparum competent strains and non-myelodepleted NOD-scid IL2Rgammanull mice engrafted with human erythrocytes". Antimicrob. Agents Chemother. 53 (10): 4533–6. doi:10.1128/AAC.00519-09. PMC 2764183. PMID 19596869.
- ↑ Mota J, Rico-Hesse R (2009). "Humanized mice show clinical signs of dengue fever according to infecting virus genotype". J. Virol. 83 (17): 8638–8645. doi:10.1128/JVI.00581-09. PMC 2738212. PMID 19535452.
- ↑ Jaiswal S; Pearson T; Friberg H et al. (2009). Unutmaz, Derya, ed. "Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice". PLoS ONE 4 (10): e7251. doi:10.1371/journal.pone.0007251. PMC 2749937. PMID 19802382.
- ↑ King M; Pearson T; Shultz LD et al. (2008). "A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene". Clin. Immunol. 126 (3): 303–14. doi:10.1016/j.clim.2007.11.001. PMID 18096436.