Accelerating Preclinical Research Using the Next-Generation of Humanized Immune System (HIS) Mouse Models

Humanized immune system mice (HIS models) have become essential tools for scientists conducting preclinical research in immunology and oncology. These next-generation models allow for more translatable evaluation of human immune responses, making them highly relevant for testing immunotherapies, understanding disease mechanisms, and bridging the gap between animal studies and clinical trials.

A recent on-demand webinar hosted by Inside Precision Medicine and sponsored by Taconic Biosciences highlighted how humanized mice are transforming the preclinical landscape.

What are Humanized Immune System Mice?

Humanized mice are immunodeficient mouse models engrafted with human immune cells or tissues, enabling researchers to model human immune function in vivo. These models are particularly useful for studying human T cells, B cells, NK cells, and other immune components in the context of various diseases, including cancer and autoimmune disorders.

There are two primary types of humanized models commonly used in research:

• PBMC-engrafted mice: Best suited for short-term studies (up to 4–8 weeks). These models support rapid human T cell expansion but lack robust B cell function and are prone to graft-versus-host disease (GVHD).
• CD34+ HSC-engrafted mice: Ideal for long-term studies. These models develop a more complete human immune system, including myeloid cell populations, but require a more extended engraftment period.

Selecting the Right Immunodeficient Mouse Strain

The success of humanized models depends heavily on the choice of immunodeficient host strain. Several backgrounds are commonly used for human xenograft studies due to varying levels of immunodeficiency:

Next-Generation Models enhance the utility of Humanized Immune Model Systems

To meet the growing demands of immunology and oncology research, several next-generation NOG strains have been developed: 

• β2m NOG: Supports extended-duration PBMC-engrafted mouse studies by knockout of the murine class I MHC. 
• Cytokine-expressing models: These cytokine-enhanced humanized mice offer improved physiological relevance and are particularly valuable for cell therapy and immuno-oncology studies.
  • NOG-EXL - Expresses human GM-CSF and IL-3, enhancing the development of both myeloid and lymphoid lineages
  • IL-6 NOG - Supports monocytes
  • IL-2 NOG - Hematologic malignancies, T cell therapies, CAR-T, and TIL
  • IL-15 NOG - NK and CAR-NK

Solving Murine Fc Receptor Interference in Humanized Models

One major challenge in HIS research is the unintended interaction between human antibodies and murine Fc gamma (Fcγ) receptors, which can lead to misleading data in therapeutic antibody studies. To address this, models such as the FcResolv® NOG mouse have been developed. By knocking out murine Fcγ receptors, this strain improves accuracy in antibody efficacy studies and eliminates false positives or negatives.

Donor Selection: A Critical Factor in Humanized Immune System Study Design

The source and quality of human donor material significantly impact study reproducibility. To help researchers optimize outcomes, access to pre-validated and pre-characterized CD34+ donors is available:

• Pre-validated donors: Previously engrafted and assessed at 10 weeks for predictable immune reconstitution.
• Pre-characterized donors: Profiled over a 30-week period, offering detailed insights into engraftment kinetics, immune cell composition, and survival rates.

Researchers can also select donors based on HLA type, sex, or ethnicity, enabling personalized and disease-specific modeling, including for GVHD research and HLA-restricted immune responses.

Flexible Humanized Immune System Research Services and Support

To meet diverse research needs, scientists can take advantage of a wide range of customization options and technical support, including:

• Donor material reservation for future studies
• Selection of HLA-typed donors for immune compatibility research
• Custom flow cytometry panel design to evaluate specific immune populations

These capabilities help streamline workflows and enhance study precision. 

Conclusion: Humanized Immune System Models as a Foundation for Translational Research

Humanized immune system models are rapidly becoming invaluable in preclinical immunology and immuno-oncology research. With advanced mouse strains, deeply characterized donor options, and customizable research services, these models enable scientists to generate more predictive, human-relevant data.

As the field continues to evolve, humanized mice will remain central to developing next-generation therapies and improving translational outcomes between bench and bedside.