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Top Tips on Selecting the “Best” Immunodeficient Mouse Model for Your Research

Immunodeficient mice are invaluable tools for immunology, infectious disease, oncology, hematopoietic, and regenerative medicine studies. They can serve as hosts for engraftment of mouse tumor cells, human cancer cell lines, patient-derived xenograft tumors, and many aspects of the human immune system. Yet, the diversity of immunodeficient mouse strains available and the nature of specialized research applications of these models increases the difficulty of choosing the “best” model for your study. Here are a few tips to help you pick out the appropriate immunodeficient mouse model.

Mouse genetic background matters

The genetic background of a strain profoundly affects the phenotype and potential applications of a mouse model. NSGTM mouse model variants are highly immunodeficient mice and widely applied in biomedical research. A critical feature of these strains is the NOD genetic background, which contributes to defects in innate immunity such as reduced natural killer (NK) cell activity, absence of circulating complement, and deficits in macrophages as well as antigen-presenting cells.

JAX distributes a variety of nude strains with a similar nomenclature: NU/J (002019) inbred mice, B6 nude (000819) congenic mice, and J: NU (007850) outbred nudes. So, what are the differences between these strains? A simple answer to this is that even though they have the same spontaneous mutation (Foxn1 nu), they all have different genetic backgrounds. Being inbred and congenic, respectively, NU/J and B6-nudes are genetically homogeneous. Consequently, they are likely to support more consistent tumor growth. In contrast, outbred J: NU nudes may exhibit more variable tumor growth because they are genetically heterogeneous. Also, outbred nude mice are more vigorous and may be able to withstand more prolonged experimental study.

Know what to expect from a mouse model

If you are interested in dissecting the mechanism of certain chemotherapies that directly target tumor cells inbred NU/J (002019) or outbred J: NU (007850) could be optimal hosts for the engraftment and growth of human cancer cell lines. In contrast, to test novel immunotherapies that modulate the human immune system, you may wish to choose NSGTM (005557), NSG-SGM3TM (013062), NSG™ -IL15 (030890), or NSG™ MHC I/II DKO (025216) as your host for co-engraftment of patient-derived tumors (PDX) and human CD34+ hematopoietic stem cells (hHSCs).

When selecting an appropriate model for your particular project, you should have clear expectations from the model, and here are some factors to consider when choosing a mouse model:

  • Endogenous immune system components. Examine the endogenous immune function of each immunodeficient model by studying the remaining function of B cells, T cells, dendritic cells, macrophages, NK cells, and the complement system. For models with intact innate immunity, such as nude mice, the presence of NK cells can prevent the homing and maintenance of human cells, thus limiting primary human cell engraftment. For models with deficiencies in multiple cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) signaling, such as NSG variants, this deficiency results in a significantly improved engraftment of human tissues, hematopoietic stem cells, and peripheral blood mononuclear cells (PBMCs). Before choosing an immunodeficient model, be sure to find out the status of the immune system components of the models. View the immunodeficient mouse and xenograft host comparisons table for a quick view of the immune system components of various strains.

  • Research type. Select an immunodeficient model that would be the best fit for your research target. For example, if you are exploring potential immune-modulation therapies that focus on specific human immune cell types or conducting research on infectious diseases that require the presence of human immune cells, hHSC humanized NSGTM, NSG-SGM3TM, or NSG™ MHC I/II DKO would be robust test platforms. However, if your goal is to detect a direct killing effect of specific chemotherapies, you might utilize the inbred nude NU/J or BALB/c-scid mice (001803) to track the response of subcutaneous or orthotopic engrafted tumors.

Understand the limitations of a model

Not surprisingly, the immune system deficiency of these models also causes additional limitations.

  • Leakiness. The scid mutation was found to render some strains susceptible to leakiness. The frequency varies depending on the genetic background, which means some of the scid mice, B6-scid (001913), for example, may produce a limited number of functional T and B cells between three and nine months of age. Consider NOD-scid (001303) mice if you are looking for scid mutant mice with little to no leakiness, or NSG mice (005557) with no leakiness at all.

  • Radiosensitivity. When investigating potential radiation therapy, a host mouse that is radioresistant may prove to be optimal. Scid mice, however, are highly radiosensitive because the mutation is in a protein involved in DNA repair. Rag1 or Rag2 KO mice, however, will tolerate a higher irradiation dose and might be preferred for some radiation therapy studies. The Rag KO mice are also less sensitive to chemotherapeutics that cause DNA damage.

  • Lifespan. For long-term engraftment studies using primary tumors that may take months to grow, it would be prudent to avoid models with a relatively short lifespan. For example, the NOD-scid mice only live for five to nine months due to the development of IL-2-dependent thymic lymphomas. Additional studies have shown that Rag1 KO mice (002216) and NSGTM mice exhibited a longer life span than NOD-scid mice. NSG™ mice can survive over a year and a half in a sufficiently clean environment with a median survival time exceeding 89 weeks. Information on model lifespans can be found in various peer-reviewed publications, or by calling JAX Technical Information Scientists (TIS).

  • Husbandry. Compared to immune-competent strains, immunodeficient strains do require special care and housing. The following blogs have detailed information on caring for immunodeficient mice:
    Six Strategies for Success Caring for Immunodeficient Mice
    What Type of Housing Conditions Do Immunodeficient Mice Need?

  • A Chinese saying about Shakespeare states, “There are a thousand Hamlets in a thousand people’s eyes.” There is not a universal “best” immunodeficient model for all the studies, but take a look at all the tips above to help you find the most optimal model for your research!

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