These will fill an extremely promising niche in human-specific immunotherapeutics of diseases such as cancer, autoimmune disease, or infections. The process of obtaining these preclinical models, however is not very easy where the production procedure ascertains this kind of therapy because both the species utilized for model-making, human, and mouse will never work similarly to be completely accurate for the immune system. Some particular interest focus is placed on humanized mouse models especially prepared by human HSCs and PBMCs. This can only be made possible in the case such models are constructed in a manner such that the researcher is able to evaluate efficiency and safety in such new immunotherapies through mechanisms of actions closely approximating human immunological functions. It is in light of this, that this paper illustrates the advantages and disadvantages of such HSC humanized and PBMC humanized models for evaluating immunotherapeutics.

Humanized Mouse Models in Immunotherapy

Humanized mouse models are immunodeficient mice engrafted with human immune cells or tissues to recapitulate some features of the human immune system. They have very recently become important tools in translational research, especially during the evaluation of novel immunotherapies. Two of the most commonly used approaches have been related to the reconstitution of immunodeficient mice with human HSCs or PBMCs.

HSC Humanized Models

These humanized models of HSCs are created by the transplantation of immunodeficient mice such as NOD scid gamma (NSG) or BALB/c-Rag2-/-γc-/- with human CD34+ hematopoietic stem cells isolated from umbilical cord blood, bone marrow, or fetal liver. The derived hematopoietic stem cells are then allowed to further differentiate into various types such as T cells, B cells, monocytes, and NK cells. This finally leads to a human-like functional immune system.

Advantages of Humanized Models with HSCs

Immune cells obtained from HSCs may have a very extended life; hence such models are suitable for chronic diseases and long-term immunotherapeutic studies.

• Human T and B cells: Can differentiate and mature in these models; hence useful to perform immune memory and vaccine response experiments.
• Physiological Representation- The immune ontogeny matures slowly with these models that are more humanly.

Limitation of HSC Humanized Model

• Inadequate Innate Immunity – Although it is quite robust in terms of adaptive immunity systems, innate immunocytes, i.e., NK cells and Monocytes, however often act somewhat suboptimally.
• Graft Variation – Due to variability caused by human sources from which those HSC’s are obtained results in variability pertaining to immune-cell reconstitution.
• Labor-Intensive Model- In these models, the human-like immune system matures only after several months, so these models for drug screening can not be promptly carried out.

PBMC Humanized Models

PBMC humanized models are developed by implanting human PBMCs, which are obtained from healthy donors, into immunodeficient mice. A human functional immune system is developed in weeks and used as a rapid track to assess immunotherapy.

Advantages of PBMC Humanized Models

• Fast Engraftment: Human immune systems take much shorter time durations in the model of PBMC as compared to that of HSC models and can thus become the best fit for immediate assessment through immunotherapy.
• Immature T Cells- In the composition of PBMC, there exist mature T cells, B cells, and monocytes contributing to an immune response after transplantation.
• Applications of PBMCs in Personalized Medicine: Since PBMCs are isolated from patients, the models have been used for patient-specific study of immune responses to therapies.

Limitations of PBMC Humanized Models

• Short Lifespan – Typically, PBMC models are short-lived because their immune cells typically survive only temporarily .
• Graft-vs-Host Disease (GvHD) – Because of the presence of mature T cells, PBMC models often suffer from GvHD, limiting the length of experiments.
• Poor Immune Development – Compared to HSC models, PBMC models do not support de novo differentiation of immune cells. Therefore, they cannot be used for full development of the immune system.

Humanization Models Applications in Immunotherapy Research

Both HSC and PBMC models have been highly used to test immunotherapies in several disease conditions.

1. Immunotherapy against Cancers

In reality, humanized mouse models are proving to be important tools for assessing cancer immunotherapy, starting from checkpoint inhibitors, CAR T cells, to bispecific antibodies. Generally speaking, the advantages of hematopoietic stem cell-based models lie in longer-term efficacy and persistence of cell therapies based on T cells. PBMC-based models have come in handy with regard to an immediate window gained in the initial screen of efficacy of checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 antibodies.

2. Infectious Disease Models

The main emphasis of HSC models is on infectious diseases, including HIV, hepatitis, and tuberculosis, which require lifelong immune responses. The models allow for the assessment of the efficacy of antiviral drugs, monoclonal antibodies, and vaccines. In contrast, PBMC models are more relevant to acute immune responses elicited by viruses, such as influenza and SARS-CoV-2.

3. Models of Autoimmune Diseases and Graft Rejection

PBMC models are used to study the autoimmune responses and test immunomodulatory therapies with rheumatoid arthritis and multiple sclerosis. HSC models are applied in transplant immunology for graft rejection mechanisms and tolerance-inducing therapies.

Future Perspectives and Conclusion

The engraftment of HSC and PBMC-based models in mice has made great strides for immunotherapy. Supporting the long-term development of immune systems, however, the ones based on HSC are suitable, whereas based on PBMC, they will be handy for drug screening that is cost effective. Areas more likely to blossom in the short term include high cytokine support, genetic manipulation for enhanced capabilities of the immunity, and models that are the hybrids of the HSC model and the one based on the PBMC system.

The more humanized the models, the more important they would be for advancing human-specific immunotherapy, which would break the bridge between preclinical research and clinical application. Such models could eventually lead to great understanding of interactions between immune cells, predict outcomes of therapies, and improve patient care.