Role of humanized immune system mice in to study the infectious and systemic inflammatory disease.
Whether the humanized immune system (HIS) mice help developing therapeutic interventions against infectious and inflammatory diseases?
Whether HIS mice may revolutionize the translational biomedical research
Whether HIS mice may revolutionize the translational biomedical research
2 Answers
ZJT
Below is an overview of the ways humanized immune system (HIS) mice are being used to model infectious and systemic inflammatory diseases, their application in therapeutic development, and how they can potentially revolutionize translational research.
1. What Are HIS Mice?
Human.zed immune system (HIS) mice are immunodeficient host strains engrafted with human hematopoietic stem cells (HSCs)—often with human thymus or liver tissue—to establish components of an intact human immune system in vivo. Standard platforms are given as:
NSG (NOD‑SCID‑γc⁻/⁻) mice with CD34⁺ HSC transplants
BLT (bone marrow–liver–thymus) mice, which receive human fetal liver, thymus, and HSC
These models recapitulate key aspects of human myeloid, B‑ and T‑lymphoid lineages, enabling human‑specific immune response experimentation not otherwise possible in conventional rodents .
2. Modeling Infectious Diseases
HIS mice are now priceless for studying human‑tropic pathogens, including:
HIV‑1 and lentiviruses: Viral entry, reservoir formation, and antiretroviral efficacy can be determined directly against human CD4⁺ T‑cells in vivo.
Dengue, Zika and other flaviviruses: Kinetics of replication, antibody-dependent enhancement, and vaccine candidates are tested against human immunity.
Mycobacterium tuberculosis: Host immune pathology and granuloma formation replicate some characteristics of human TB, allowing new antibiotics or host-directed therapy testing.
SARS-CoV-2: HIS mice expressing human ACE2 allowed probing of immune correlates of protection in addition to testing monoclonal antibodies and vaccines.
3. Modeling Systemic Inflammatory Diseases
HIS mice also enable mechanistic and therapeutic studies in the dysregulated human immunity disorders:
Sepsis and endotoxemia: Human cytokine storm signatures (e.g., IL‑6, TNF‑α) and anti‑cytokine biologic drug testing (anti‑IL‑6R, anti‑TNF) can be modeled more faithfully than in mouse‑only models .
Graft‑versus‑host disease (GVHD): Human peripheral blood mononuclear cell transplantation into NSG mice models T‑cell–mediated tissue injury, which is amenable to screening immunomodulators.
Autoimmunity (e.g., rheumatoid arthritis, IBD): Engraftment of patient‑derived immune cells can reproduce signature features (joint inflammation, gut pathology) to support targeted therapies like JAK inhibitors or TNF blockers.
4. Accelerating Therapeutic Development
By offering a human‑specific platform, HIS mice de‑risk preclinical pipelines and have already contributed to:
Antibody discovery & optimization: In vivo development of human B‑cells facilitates selection of high‑affinity, class‑switched monoclonals.
Cellular therapies: Engraftment assays of CAR‑T cells, regulatory T‑cells, and NK‑cell can predict efficacy and off‑target toxicity before clinical trials.
Small‑molecule and biologic screening: Immunotoxicity and pharmacodynamics profiles in a human immune context improve translational fidelity.
5. Limitations and Current Challenges
Insufficient myeloid and lymphoid maturation: Certain innate cell types (e.g., tissue‑resident macrophages) remain poorly reconstituted.
HLA mismatch and cytokine cross-reactivity: Murine stromal milieus may not provide accommodation for all human cytokine interactions, requiring "human cytokine knock‑in" strains.
Technical complexity and cost: Engraftment protocol and harboring of extremely immunodeficient mice mandate special facilities.
Ongoing advances—co‑transplantation of human fetal thymus, human cytokine expression (e.g., IL‑3, GM‑CSF), and HLA‑transgenic hosts—are increasingly addressing these issues.
6. Will HIS Mice Revolutionize Translational Research?
Yes, in several key ways:
Bridging the species gap: Through modeling human-specific immune function, HIS mice reduce reliance on inaccurate rodent-to-human extrapolation.
Personalized medicine: Autologous immune cell-engrafted patient-derived xenografts allow "avatar" immunotherapy and vaccine testing.
Accelerated go/no-go decisions: Rapid in vivo confirmation of human-targeted candidates can conserve time and money in drug development.
As these models continue to evolve—especially with improved human cytokine milieus and multi-organ humanization—they will shortly become the gold standard for preclinical evaluation of anti-infectives, immunomodulators, and cell-based therapies.
1. What Are HIS Mice?
Human.zed immune system (HIS) mice are immunodeficient host strains engrafted with human hematopoietic stem cells (HSCs)—often with human thymus or liver tissue—to establish components of an intact human immune system in vivo. Standard platforms are given as:
NSG (NOD‑SCID‑γc⁻/⁻) mice with CD34⁺ HSC transplants
BLT (bone marrow–liver–thymus) mice, which receive human fetal liver, thymus, and HSC
These models recapitulate key aspects of human myeloid, B‑ and T‑lymphoid lineages, enabling human‑specific immune response experimentation not otherwise possible in conventional rodents .
2. Modeling Infectious Diseases
HIS mice are now priceless for studying human‑tropic pathogens, including:
HIV‑1 and lentiviruses: Viral entry, reservoir formation, and antiretroviral efficacy can be determined directly against human CD4⁺ T‑cells in vivo.
Dengue, Zika and other flaviviruses: Kinetics of replication, antibody-dependent enhancement, and vaccine candidates are tested against human immunity.
Mycobacterium tuberculosis: Host immune pathology and granuloma formation replicate some characteristics of human TB, allowing new antibiotics or host-directed therapy testing.
SARS-CoV-2: HIS mice expressing human ACE2 allowed probing of immune correlates of protection in addition to testing monoclonal antibodies and vaccines.
3. Modeling Systemic Inflammatory Diseases
HIS mice also enable mechanistic and therapeutic studies in the dysregulated human immunity disorders:
Sepsis and endotoxemia: Human cytokine storm signatures (e.g., IL‑6, TNF‑α) and anti‑cytokine biologic drug testing (anti‑IL‑6R, anti‑TNF) can be modeled more faithfully than in mouse‑only models .
Graft‑versus‑host disease (GVHD): Human peripheral blood mononuclear cell transplantation into NSG mice models T‑cell–mediated tissue injury, which is amenable to screening immunomodulators.
Autoimmunity (e.g., rheumatoid arthritis, IBD): Engraftment of patient‑derived immune cells can reproduce signature features (joint inflammation, gut pathology) to support targeted therapies like JAK inhibitors or TNF blockers.
4. Accelerating Therapeutic Development
By offering a human‑specific platform, HIS mice de‑risk preclinical pipelines and have already contributed to:
Antibody discovery & optimization: In vivo development of human B‑cells facilitates selection of high‑affinity, class‑switched monoclonals.
Cellular therapies: Engraftment assays of CAR‑T cells, regulatory T‑cells, and NK‑cell can predict efficacy and off‑target toxicity before clinical trials.
Small‑molecule and biologic screening: Immunotoxicity and pharmacodynamics profiles in a human immune context improve translational fidelity.
5. Limitations and Current Challenges
Insufficient myeloid and lymphoid maturation: Certain innate cell types (e.g., tissue‑resident macrophages) remain poorly reconstituted.
HLA mismatch and cytokine cross-reactivity: Murine stromal milieus may not provide accommodation for all human cytokine interactions, requiring "human cytokine knock‑in" strains.
Technical complexity and cost: Engraftment protocol and harboring of extremely immunodeficient mice mandate special facilities.
Ongoing advances—co‑transplantation of human fetal thymus, human cytokine expression (e.g., IL‑3, GM‑CSF), and HLA‑transgenic hosts—are increasingly addressing these issues.
6. Will HIS Mice Revolutionize Translational Research?
Yes, in several key ways:
Bridging the species gap: Through modeling human-specific immune function, HIS mice reduce reliance on inaccurate rodent-to-human extrapolation.
Personalized medicine: Autologous immune cell-engrafted patient-derived xenografts allow "avatar" immunotherapy and vaccine testing.
Accelerated go/no-go decisions: Rapid in vivo confirmation of human-targeted candidates can conserve time and money in drug development.
As these models continue to evolve—especially with improved human cytokine milieus and multi-organ humanization—they will shortly become the gold standard for preclinical evaluation of anti-infectives, immunomodulators, and cell-based therapies.
Ian James Martins