![]() These models have been instrumental in studying human diseases, immune responses, and therapeutic interventions. Mice with such human genes are technically human-animal hybrids.Įngrafting 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. To circumvent this limitation, the next development came with the introduction of transgenes encoding for HLA I and HLA II in the NSG RAG null model that enabled buildout of human T-lymphocyte repertoires as well as the respective immune responses. In accordance to this limitation, the human T cells when engrafted in the mice, failed to recognize human antigen-presenting cells, which consequated in defective immunoglobulin class switching and improper organization of the secondary lymphoid tissue. The limitation with this model was that it lacked the human leukocyte antigen. Researchers evolved this NSG model by knocking out the RAG1 and RAG2 genes ( recombination activation genes), resulting into the RAG null version of the NSG model that was devoid of major cells of the immune system including the natural killer cells, B lymphocytes and T lymphocytes, macrophages and dendritic cells, causing the greatest immunodeficiency in mice models so far. This accounted for the creation of the NOD- scid-γcnull mice (NCG, NSG or NOG) models which were found to have defective signaling of interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Nevertheless, a major breakthrough in this field came with the introduction of the mutant IL-2 receptor ( IL2rg) gene in the NOD- scid model. This mouse model permitted for a slightly higher level of human cell reconstitution. This resulted in the creation of the NOD- scid mice which lacked T cells, B cells, and NK cells. The next big step in the development of humanized mice models came with transfer of the scid mutation to a non-obese diabetic mouse. 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. 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. ![]() As a result, they did not exhibit a rejection response to allogeneic tissue. These mice primarily produced IgM and had minimal or no IgA. Nude mice were the earliest immunodeficient mouse model. 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. Dysfunctional PRKDC gene leads to impaired development of T and B lymphocytes which gives rise to severe combined immunodeficiency (SCID). A mutation in the Foxn1 gene on chromosome 11 resulted in impaired thymus development, leading to a deficiency in mature T lymphocytes. The PRKDC gene product is necessary for resolving breaks in DNA strands during the development of T cells and B cells. The first such mouse model was derived by backcrossing C57BL/Ka and BALB/c mice, featuring a loss of function mutation in the PRKDC gene. The discovery of the athymic mouse, commonly known as the nude mouse, and that of the SCID mouse were major events that paved the way for humanized mice models. Such mouse models have also become an integral aspect of preclinical biomedical research. To overcome these limitations and to realize the full potential of animal models to enable researchers to get a clear picture of the nature and pathogenesis of immune responses mounted against human-specific pathogens, humanized mouse models have been developed. Nevertheless, there are several incongruencies of these animal systems with those of humans, especially with regard to the components of the immune system. In particular, small animals such as mice are advantageous in such studies owing to their small size, brief reproductive cycle, easy handling and due to the genomic and physiological similarities with humans moreover, these animals can also be genetically modified easily. A lot of our knowledge about several human biological processes has been obtained from studying animal models like rodents and non-human primates. Ī humanized mouse or a humanized mouse model is one that has been xenotransplanted with human cells and/or engineered to express human gene products, so as to be utilized for gaining relevant insights in the in vivo context for understanding of human-specific physiology and pathologies. Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics. ![]() Mouse carrying functioning human genes, etc.Ī humanized mouse is a genetically modified mouse that has functioning human genes, cells, tissues and/or organs.
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