Scid mice overview
Scid mice are important tools for researching hematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer, vaccine development, and regenerative medicine in vivo. So-called because of their severe combined immunodeficiency, scid mice have reduced ability to reject allogeneic or xenogeneic tissue grafts, and are therefore excellent hosts for human cells and tissues. Because some scid mice have such a superior ability to engraft and support the development of human tissues and microenvironments (e.g., primary human tumors with intact stroma, a functional human immune system), they can be "humanized."
The common denominator of all scid mice is a spontaneous loss-of-function mutation of the protein kinase, DNA activated, catalytic polypeptide (Prkdc) gene. The scid mutation was first identified in a BALB/c congenic strain (C.B-17), and it has been bred onto a variety of different genetic backgrounds. As part of their nomenclature, all scid mice contain the allele symbol "Prkdcscid."
Prkdc functions in double-stranded DNA break repair and in recombining the variable (V), diversity (D), and joining (J) segments of immunoglobulin and T cell receptor genes. Because scid mice cannot complete V(D)J gene recombination, their T and B cells do not mature and therefore cannot develop cell mediated and humoral adaptive immune responses. The penetrance of the scid mutation varies among genetic backgrounds, and some scid strains are designated “leaky” because, with age, they produce some immunoglobulin, B cells, and T cells.
Because homozygous scid mice cannot repair double-stranded DNA breaks, many are highly susceptible to genotoxic radiation damage, develop thymomas at a relatively early age, and die prematurely. Scid-associated leakiness and premature death are accelerated by the preconditioning radiation necessary to optimize the engraftment of human hematolymphoid cells. The engraftment ability of scid mice depends on the degree to which various innate immune components, such as complement, myeloid cells, and, perhaps most importantly, natural killer (NK) cells, are functional in their genetic background.
By transferring the scid mutation (either alone or with other mutations and/or transgenes) to various backgrounds, a variety of scid mice has been produced, each with unique engraftment properties and research applications. For example, some are more tolerant of radiation and live longer, some are not leaky, some are better suited for vaccine development, some are better suited for HIV/AIDS research, and some can be better humanized. One of our scientists, Professor Leonard Schultz, has been a pioneer in developing many of our scid and humanized mice. Following are brief descriptions of our five most popular models.
NSG mouse
Strain NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557), commonly known as NOD scid gamma (NSG), is the latest breakthrough in the development of immunodeficient models. It combines the innate immunity deficiencies of the NOD/ShiLtJ background, the scid mutation, and IL2 receptor gamma chain (Il2rg) deficiency. The latter two deficiencies combine to eliminate mature T cells, B cells, and NK cells. Because the Il2rg knockout prevents the development of lymphoma, NSG mice survive longer than other scid strains, enabling long-term experiments.
Engraftment of human hematopoietic stem cells and peripheral-blood mononuclear cells in NSG mice is greater than in any other mouse strain. Recent publications have demonstrated this strain’s outstanding utility for studying hematopoiesis, infectious disease, islet transplantation, leukemia, and primary tumor-stromal cell interactions in situ.
NOD scid
One of the earlier scid mouse models, the NOD scid – NOD.CB17-Prkdcscid/J strain (001303) – was constructed by transferring the Prkdcscid mutation to the Non Obese Diabetic (NOD/ShiLtSz) strain. The NOD background has numerous features that improve human tissue engraftment: it lacks complement activity, has defects in myeloid development and antigen presentation, and has low natural killer (NK) cell activity. Because it lacks T and B cells (both critical for adaptive immune responses) and has reduced innate immunity it can better engraft human hematolymphoid cells than either the BALB/c scid or B6 scid strains. Traditionally, it has been used to study the functions of human hematopoietic stem cells (HSCs) and mature lymphoid cells in vivo.
The NOD scid strain is radiosensitive, has a high incidence of thymomas, a short lifespan, and suboptimal reconstitution with human HSCs.
BALB scid
Another early scid mouse model (and still very popular with many researchers) is the BALB scid strain, CBySmn.CB17-Prkdcscid/J (001803). BALB scid was constructed by transferring the Prkdcscid mutation to the BALB/cBySmn strain, and it has reduced B and T cells. Being more immunodeficient than Foxn1nu (“nude”) mutants, it supports better engraftment of allogeneic and xenogeneic cells, tissues, and tumors. It develops three times fewer thymomas than the NOD scid, and, for certain experiments, its MHC haplotype may be more appropriate than that of the NOD scid.
Unlike NOD scid, the BALB scid strain is leaky with age and retains more components of the innate immune system, including normal complement activity, normal numbers and functions of macrophages, NK cells, and APCs. BALB scid is radiosensitive, has a short lifespan (due to thymomas), and supports significantly less engraftment of human cells and tissues than the NOD scid.
B6 scid
The B6 scid – strain B6.CB17-Prkdcscid/SzJ (001913) – was produced by transferring the Prkdcscid mutation to the C57BL/6J (000664) strain. B6 scid mice lack most B and T cells. B6 scid is more severely immunodeficient and supports better engraftment of allogeneic and xenogeneic cells, tissues, and tumors than Foxn1nu mutant strains.
The B6 scid strain is very leaky with age, has high NK cell and complement activity, and retains normal APC functions.
NOD.Cg-Prkdcscid B2mtm1Unc/J
This strain accepts human hematopoietic stem cell grafts and T cells better than NOD scid. It was produced by transferring the beta-2 microglobulin (B2m) knockout to the NOD scid strain. Because it does not express MHC class I molecules on its cell surfaces, it has very low levels of NK cell activity.
NOD.Cg-Prkdcscid B2mtm1Unc/J (002570) develops more thymomas and at an earlier onset than NOD scid. Additionally, use of this strain for long-term experiments is limited because it accumulates iron in the liver, is more radiosensitive, and dies earlier than NOD scid. PBMC engraftment results in high levels of human T but not B cells. Reconstitution with human cells and tissues is less efficient than in the NSG strain. It is difficult to breed.
In all, we distribute more than 30 strains of scid mice, and several more are under development. You can easily find them in the JAX® Mice Database by using the Allele Symbol search term "scid."
To help researchers choose scid mice most appropriate for their research, we have developed the following resources:
Selected References
(The JAX® Mice Database has complete reference lists for each strain)
Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R. 2005. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174:6477-89.
Macchiarini F, Manz MG, Palucka AK, Shultz LD. 2005. Humanized mice: are we there yet? J Exp Med 202:1307-11.
Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL, Leiter EH. 1995. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol 154: 180-91.
Shultz LD, Ishikawa F, Greiner D. 2008. Humanized mice in translational biomedical research. Nat Rev Immunol 7:118-30.
