NOG mice are a specialized laboratory mouse model developed for biomedical research. They possess a severely compromised immune system, making them highly suitable for engrafting human cells and tissues. This allows scientists to study human diseases and biological processes within a living system, providing insights not possible with traditional cell cultures or less immunodeficient animal models. Their development has advanced medical investigation.
Genetic Origins of NOG Mice
NOG mice were created through the combination of genetic material from three mouse strains. This began with the NOD/Shi inbred strain, known for its unique variant of signal regulatory protein alpha (SIRPα). SIRPα helps engrafted human cells avoid elimination by mouse macrophages. The NOD/Shi mouse also contributes to a reduced innate immune response, including macrophage dysfunction and defects in complement hemolytic activity.
The second genetic contribution comes from mice with Severe Combined Immunodeficiency (SCID). SCID mice have a recessive mutation in the Prkdc gene, which makes the DNA-dependent protein kinase enzyme ineffective. This genetic defect prevents the proper development of T and B lymphocytes, rendering these mice unable to mount adaptive immune responses.
Finally, the IL-2Rγnull mutation was introduced, targeting the interleukin-2 receptor gamma chain. This chain is a component of receptors for several cytokines necessary for the development and maturation of various immune cells. The NOG mouse was developed by combining a C57BL/6J-IL-2Rγnull mouse with a NOD/Shi-scid mouse, resulting in a mouse with extremely severe combined immunodeficiency.
Immune System Deficiencies
The combined genetic modifications in NOG mice lead to significant deficiencies in their immune system. They exhibit a lack of functional T and B cells, primary components of adaptive immunity. This absence of T and B lymphocytes is a direct result of the Prkdc mutation, preventing the necessary DNA recombination for their development.
NOG mice also lack Natural Killer (NK) cell activity, a part of the innate immune system. This deficiency stems from the IL-2Rγnull mutation, as the common gamma chain is required for NK cell development. NOG mice also show reduced complement activity and have dysfunctional macrophages and dendritic cells, other components of the innate immune response. These immune system impairments mean NOG mice do not reject foreign cells or tissues.
Research Applications
NOG mice are used in oncology and cancer research as models for human tumor xenografts. Researchers can engraft human tumor cells into these mice to study tumor growth, metastasis, and the effectiveness of new anti-cancer therapies. This allows evaluation of drug candidates and treatment strategies in a living system that mimics human disease.
In immunology and infectious disease research, NOG mice create “humanized” mouse models by engrafting human cells. These humanized mice develop human immune cells, enabling the study of human immune cell development, function, and responses to pathogens. This provides an in vivo platform to investigate human-specific immune responses and evaluate vaccines or antiviral drugs.
Regenerative medicine also benefits from NOG mice, as their immunodeficient status allows for the study of human stem cell differentiation and tissue regeneration without immune rejection. Scientists can transplant human stem cells into these mice and observe their development into various cell types and tissues, gaining insights into tissue repair and organ development. This application aids in understanding how human cells behave in a living environment and contributes to the development of regenerative therapies.
NOG mice also facilitate drug development by providing a living system to test new drugs on human cells or tissues. This includes evaluating the efficacy and safety of novel therapeutics before human clinical trials. Testing drugs in a humanized environment can provide more predictive data, accelerating preclinical research for various conditions.