Immunology

An Introduction to Common Immunodeficient Mouse Models

Q: What is the engraftment efficiency across tumor types?

Cyagen models achieve >80% success for hematologic malignancies and 60–75% for solid tumors (e.g., breast, lung). Variability aligns with human tumor biology rather than model limitations.

Q: What is the process for establishing human tumor xenografts in immunodeficient mice?

The establishment of human tumor xenografts follows a standardized preclinical workflow designed to maintain the biological integrity of the human tumor in an in vivo environment: Selection of Host Model: Depending on the tumor’s aggressiveness and the study's requirements, an appropriate immunodeficient strain is selected. Options range from BALB/c Nude mice (T-cell deficient) to highly immunodeficient models like NKG (T, B, and NK-cell deficient), which are ideal for difficult-to-engraft samples. Preparation of Inoculum: * CDX (Cell Line-derived): Human cancer cell lines are cultured, harvested, and suspended in a serum-free medium or a basement membrane matrix (e.g., Matrigel) to enhance engraftment. PDX (Patient-derived): Freshly archived patient tumor fragments are processed and kept in a cold preservation medium before immediate transplantation. Inoculation/Transplantation: The material is typically injected subcutaneously (into the flank) for easy monitoring, or orthotopically (into the organ of origin) to better simulate the natural tumor microenvironment and metastatic potential. Monitoring and Validation: Once the "take" is successful, tumor growth is monitored using calipers or non-invasive imaging (e.g., bioluminescence). The model is validated through histopathological analysis (H&E staining) to ensure the xenograft retains the characteristics of the original human tumor.

Q: Why are immunodeficient mice required for establishing human tumor xenograft models?

Immunodeficient mice are essential for human tumor xenograft models (including both CDX and PDX) due to the biological principle of immune rejection: Preventing Graft Rejection: A standard mouse with a functional immune system would recognize human cancer cells or tissues as "foreign" invaders. Its T-cells, B-cells, and Natural Killer (NK) cells would immediately attack and destroy the human cells, preventing any tumor growth. Creating a "Permissive" Environment: By using specialized strains like BALB/c Nude, NOD Scid, or NKG, we remove these immune barriers. This creates a permissive environment that allows the human "graft" to survive, develop a blood supply (angiogenesis), and proliferate as a solid tumor. Enabling Preclinical Accuracy: These models allow researchers to study the behavior of actual human cancer within a living system (in vivo). Without immunodeficient hosts, it would be impossible to evaluate the efficacy of human-specific anti-cancer therapies before they move toward the drug development pipeline.

Q: How has the development of immunodeficient mice evolved over the years?

The journey began with the discovery of the Athymic Nude mouse in the 1960s, which lacked T-cells. While revolutionary, these mice retained functional B and NK cells, limiting the types of human tissues they could accept. The improvement continued with the NOD Scid model, which addressed B-cell deficiency but was hindered by "leakiness" (residual immune activity) and a short lifespan. The major breakthrough came with the development of highly immunodeficient models, such as Cyagen’s NKG mouse. By knocking out the Il2rg gene on a NOD Scid background, researchers successfully eliminated T, B, and NK cells, creating the most receptive host for human cell engraftment to date.

Q: What were the key technical improvements in the latest generation of immunodeficient mice?

Modern improvements focus on three core areas: Longevity: Unlike older Scid models, the new generation (like NKG ) does not suffer from thymic lymphomas, allowing for long-term studies exceeding 12 months. Stability: Elimination of "leakiness" ensures that the mice do not spontaneously develop functional murine T or B cells as they age. Support for Humanization: The latest models are engineered to express specific human cytokines (e.g., IL-15, GM-CSF) to better support the survival and differentiation of specialized human immune cell subsets.

Q: Are BALB/c mice considered immunodeficient models?

No, standard BALB/c mice are immunocompetent, meaning they have a complete and functional immune system, including T-cells, B-cells, and Natural Killer (NK) cells. However, confusion often arises because the BALB/c Nude mouse—a popular immunodeficient model—is derived from the BALB/c background. Here is the breakdown: BALB/c (Wild-type): An immunocompetent inbred strain. It is widely used in immunology, inflammation, and vaccine research because it naturally biases toward a Th2 immune response. BALB/c Nude (Foxn1 ): An immunodeficient variant. Due to a mutation in the Foxn1 gene, these mice lack a thymus and cannot produce mature T-cells. They are also hairless, which is their most defining physical characteristic.

Cyagen Technical Content Team | June 11, 2025

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Contents

01. Types of Immunodeficient mice

Immunodeficient mice refer to the mice with defects in one or more immune components (such as T, B, NK cells) in the immune system. This type of mouse is widely used in the research of oncology (tumor growth, metastasis, anti-tumor drug screening), immunology (mechanisms of immune cell development and proliferation, pathology of immune diseases), infectious diseases (pathogenic mechanisms of viral/bacterial infectious diseases), and stem cell biology (human stem cell transplantation), and more.

Types of Immunodeficient mice

Nude mice

In 1962, the first mouse with immune dysfunction was found at Ruchill Hospital in Glasgow. They are called nude mice because they are hairless.

The FOXN1 gene is absent in nude mice. Lack of a functional thymus and T lymphocytes results in their adaptive immune response defected (including T cell-mediated immune response and helper T cell-mediated antibody formation). This means that they usually do not reject homologous transplants or xenografts, so nude mice are commonly used as recipients of human tumor xenografts.

However, nude mice still have B cells and NK cells (their NK cells are more active than wild-type mice), and the complete innate immunity to some extent limits the human cancer transplantation in nude mice. In addition, T cell leakage appears alongside aging of nude mice.

NOD-SCID mice

In 1980, Makino (Japan) found that non obese diabetic (NOD) mice suffered from T lymphocyte infiltration and islets β cell mass reduction, a hallmark of Type 2 Diabetes, which was accompanied with a variety of immune abnormalities, including complement deficiency and dysfunction of NK cells, macrophages, and dendritic cells.

In 1995, Shultz established non-obese diabetic (NOD)-severe combined immunodeficiency (SCID) mice by hybridizing NOD and SCID mice. NOD-SCID mice do not develop diabetes, lack T cells and B cells, and have inherent immune deficiency, so they become an ideal transplant recipients of human hematopoietic stem cells and human solid tumors.

In addition, Shultz et al. found that the immune leakage of SCID mice was as high as 90%, while that of NOD-SCID mice was less than 10%. As such, NOD-SCID mice have quickly become an indispensable transplantation model in hematopoietic cell research.

C-NKG mice

C-NKG mouse is a severely immune deficient strain independently developed with Targeted Gene Editing-Pro to achieve IL2RG gene knockout on NOD/Shi-Scid mice.

Features:

Lacking mature T, B and NK immune cells
The activity of complement is decreased
The phagocytosis of macrophages to human cells is weak

C-NKG mice facilitate highly efficient human tumor cell line xenotransplantation (CDX) and human tumor tissue xenotransplantation (PDX). A variety of tissues can be efficiently transplanted into these mice, including human blood stem cells (HSC), peripheral blood mononuclear cells (PBMC), and more.

At present, the C-NKG model is recognized for a high degree of immunodeficiency for modeling tumors, immunity, autoimmune diseases, immunotherapy vaccine, GVHD / transplantation, safety evaluations and other research.