Humanized mouse

Source: Wikipedia, the free encyclopedia.

A humanized mouse is a genetically modified mouse that has functioning human genes, cells, tissues and/or organs.[1] Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics.[2]

A humanized mouse or a humanized mouse model is one that has been

preclinical biomedical research.[4]

History

The discovery of the athymic mouse, commonly known as the

PRKDC gene. The PRKDC gene product is necessary for resolving breaks in DNA strands during the development of T cells and B cells. A mutation in the Foxn1 gene on chromosome 11 resulted in impaired thymus development, leading to a deficiency in mature T lymphocytes. Dysfunctional PRKDC gene leads to impaired development of T and B lymphocytes which gives rise to severe combined immunodeficiency (SCID). In spite of the efforts in developing this mouse model, poor engraftment of human hematopoietic stem cells (HSCs) was a major limitation that called for further advancement in the development humanized mouse models.[5]
Nude mice were the earliest immunodeficient mouse model. These mice primarily produced IgM and had minimal or no IgA. As a result, they did not exhibit a rejection response to allogeneic tissue. Commonly utilized strains included BALB/c-nu, Swiss-nu, NC-nu, and NIH-nu, which were extensively employed in the research of immune diseases and tumors. However, due to the retention of B cells and NK cells, they were unable to fully support engraftment of human immune cells, thus making them unsuitable as an ideal humanized mouse model.

The next big step in the development of humanized mice models came with transfer of the scid mutation to a non-obese diabetic mouse. This resulted in the creation of the NOD-scid mice which lacked

secondary lymphoid tissue.[6]

To circumvent this limitation, the next development came with the introduction of transgenes encoding for HLA I and HLA II in the NSG RAGnull model that enabled buildout of human T-lymphocyte repertoires as well as the respective immune responses.

human-animal hybrids
.

Types

Engrafting an immunodeficient mouse with functional human cells can be achieved by

intravenous injections of human cells and tissue into the mouse, and/or creating a genetically modified mouse
from human genes. These models have been instrumental in studying human diseases, immune responses, and therapeutic interventions. This section highlights the various humanized mice models developed using the different methods.

Hu-PBL-scid model

The human peripheral blood lymphocyte-severe combined immunodeficiency mouse model has been employed in a diverse array of research, encompassing investigations into Epstein-Barr virus (EBV)-associated lymphoproliferative disease, toxoplasmosis, human immunodeficiency virus (HIV) infection, and autoimmune diseases.

myeloid cells. Other limitations with this model are that it is suitable for use only in short-term experiments (<3 months) and the possibility that the model itself might develop graft vs. host disease.[7]

Hu-SRC-scid model

The humanized severe combined immunodeficiency (SCID) mouse model, also known as the hu-SRC-scid model, has been extensively utilized in various research areas, including immunology, infectious diseases, cancer, and drug development. This model has been instrumental in studying the human immune response to xenogeneic and allogeneic decellularized biomaterials, providing valuable insights into the biocompatibility and gene expression regulation of these materials.

polymorphonuclear leukocytes, and megakaryocytes.[7]

BLT (bone marrow/liver/thymus) model

The BLT model is constituted with human

kidney capsule and by transplantation of HSCs obtained from fetal liver. The BLT model has a complete and totally functional human immune system with HLA-restricted T lymphocytes. The model also comprises a mucosal system that is similar to that of humans. Moreover, among all models the BLT model has the highest level of human cell reconstitution.[13]

However, since it requires surgical implantation, this model is the most difficult and time-consuming to develop. Other drawbacks associated with the model are that it portrays weak immune responses to

GvHD.[7]

Transplanted human organoids

Bio- and electrical engineers have shown that human cerebral organoids transplanted into mice functionally integrate with their visual cortex.[14][15] Such models may raise similar ethical issues as organoid-based humanization of other animals.

Mouse-human hybrid

A mouse-human hybrid is a

white blood cells into them in order to study immune system responses.[7] One such application is the identification of hepatitis C virus (HCV) peptides that bind to HLA, and that can be recognized by the human immune system, thereby potentially being targets for future vaccines against HCV.[16]

Established models for human diseases

Several mechanisms underlying human maladies are not fully understood. Utilization of humanized mice models in this context allows researchers to determine and unravel important factors that bring about the development of several human diseases and disorders falling under the categories of infectious disease, cancer, autoimmunity, and GvHD.

Infectious diseases

Among the human-specific infectious pathogens studied on humanized mice models, the

human immunodeficiency virus has been successfully studied.[7] Besides this, humanized models for studying Ebola virus,[17] Hepatitis B,[18] Hepatitis C,[19] Kaposi's sarcoma-associated herpesvirus,[20] Leishmania major,[21] malaria,[22] and tuberculosis[23]
have been reported by various studies.

NOD/scid mice models for

influenza virus[26]
have also been developed.

Cancers

On the basis of the type of human cells/tissues that have been used for engraftment, humanized mouse models for

subcutaneous, intravenous or intra-pancreatic injections) with patient-derived pancreatic cancer tumors[31] have also been developed for the study of leukemia and pancreatic cancer respectively. Several other humanized rodent models for the study of cancer and cancer immunotherapy have also been reported.[32]

Autoimmune diseases

Problems posed by the differences in the human and rodent immune systems have been overcome using a few strategies, so as to enable researchers to study

PBMCs and administered with myelin antigens in Freund's adjuvant, and antigen-pulsed autologous dendritic cells have been used to study multiple sclerosis.[33] Similarly, NSG mice engrafted with hematopoietic stem cells and administered with pristane have been used for studying lupus erythematosus.[34] Furthermore, NOG mice engrafted with PBMCs has been used to study mechanisms of allografts rejection in vivo.[35]
The development of humanized mouse models has significantly advanced the study of autoimmune disorders and various areas of immunology and disease research. These models have provided a platform for investigating human diseases, immune responses, and therapeutic interventions, bridging the gap between human and rodent immune systems and offering valuable insights into disease pathogenesis and potential therapeutic strategies.

See also

References

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Further reading

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