Role of humanized immune system mice in to study the infectious and systemic inflammatory disease.

Although it appear amazing, but there we'll be still a difference than human in any way. That wil not allowing as to escape the clinical trial before any new agent.

A fundamental understanding of many biological processes in humans has stemmed from experimental studies in animal models, particularly in rodents. Using these models, key aspects of the development and regulation of the haematopoietic and immune systems have been elucidated at the cellular and molecular levels. However, many aspects of mammalian biological systems, particularly their immune systems, are species specific. Moreover, rodents are refractory to certain human specific infectious agents, and many of the new therapeutic and immunomodulatory reagents that have been developed are human specific.  For many years, investigators have relied on chimpanzees to bridge the final gap between rodent models and humans. However, the use of chimpanzees for biomedical research has been banned in Europe, and a recent NIH directive has stopped all new research on chimpanzees in the United States. Based on these restrictions it is unclear whether experimentation in chimpanzees will be a feasible approach in the future for moving discoveries made in rodents through the pre-clinical phase to human trials. Therefore, to address the limitations of translating discoveries in rodents into clinical applications, sophisticated small animal models that more closely recapitulate human biological systems, termed “humanized” mice, are more acutely required. Experiments using humanized mice, or any animal model system, need to be designed to address a mechanistic question rather than attempting to fully recapitulate the human biological process or pathology. With these caveats in mind, humanized mice are becoming increasing important tools in translational biomedical research, permitting insights into our understanding of human hematopoiesis, innate and adaptive immunity, autoimmunity, infectious disease and cancer immunology.

Humanized immune system (HIS) mouse models have been invaluable in the development and pre-clinical validation of therapeutic modalities for example cell based therapies. For example HIS mouse is used to test CAR-T drug products and their iteration. However not all products can be tested in murine model. for example there is not a good way to test monocyte derived DC based therapies in mice. another example is development of modalities for infectious agents due to lack of murine orthologs. this may become increasingly difficult going forward due to a call for 3Rs to reduce, replace and refine animal use. For example FDA just eliminated the need to a 6 months toxicity studies in mouse for monoclonal antibodies since those are not showing to be very predictive of toxicity profile which can be detected only in early Phase I clinical trials. 

while no murine model can serve as a direct replica for human disease, most murine models recapitulate specific mechanisms and processes involved in health an disease.

HIS mice will only be as good as the questions they are used to answer.

Answer:

Humanized immune system (HIS) mice are indispensable tools for investigating infectious and systemic inflammatory diseases, as they provide a more physiologically relevant model compared to conventional murine systems. By engrafting immunodeficient mice (such as NSG or NOG strains) with human hematopoietic stem cells or peripheral blood mononuclear cells, these animals develop functional human immune components, including T cells, B cells, monocytes, and dendritic cells.


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1. Modeling Human-Specific Immune Responses

HIS mice allow researchers to study human-pathogen interactions that cannot be replicated in normal mouse models, especially for viruses with strict human tropism (e.g., HIV, HBV, EBV, dengue).

They provide insight into cytokine signaling, T-cell responses, and antibody production, thereby reflecting human immune regulation.



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2. Studying Infectious Diseases

Used to evaluate pathogen persistence, latency, and immune evasion strategies.

Facilitate preclinical testing of antivirals, vaccines, and immunotherapies.

For example, HIS mice have been critical in understanding HIV reservoirs and vaccine-induced immunity.



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3. Investigating Systemic Inflammatory Disorders

HIS mice recapitulate aspects of human immune dysregulation such as cytokine storms, autoantibody formation, and T-cell mediated pathology.

They are widely used to study mechanisms of sepsis, autoimmune diseases, and graft-versus-host disease.



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4. Translational Relevance

HIS models help bridge the gap between in vitro studies and human clinical trials.

They allow testing of human-targeted biologics (e.g., anti-cytokine antibodies, checkpoint inhibitors) that would not cross-react with murine immune proteins.



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Conclusion

Humanized immune system mice are powerful platforms for exploring both infectious agents and systemic inflammatory conditions. They enable mechanistic insights into human immunity, serve as preclinical models for therapeutic evaluation, and provide translational value where conventional mouse models fail to capture human-specific disease pathways.

The authors provide 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.

Comment

The authors may check in these HIS mice that critical genes for survival such as Sirtuin 1 are not inactivated. Sirtuin 1 is important to the immune system and the prevention of multiple organ disease syndrome and systemic inflammatory diseases. Sirtuin 1 activation is required in these HIS mice.

RELEVANT REFERENCES:

1.      Anti-Aging Genes Improve Appetite Regulation and Reverse Cell Senescence and Apoptosis in Global Populations. Advances in Aging Research, 2016, 5, 9-26.

2.      Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome. J Clin Epigenet. 2017;Vol. 3 No. 3:24. 

3.      Nutrition Therapy Regulates Caffeine Metabolism with Relevance to NAFLD and Induction of Type 3 Diabetes. J Diabetes Metab Disord. 2017; 4: 019.