The Non-Obese Diabetic (NOD) mouse is a strain of laboratory animal developed in Japan in 1980 from a line of mice being studied for cataracts. This strain is recognized globally for its application in studying autoimmune disorders. Its primary use is as a model for conditions where the body’s immune system attacks its own tissues, allowing scientists to investigate autoimmunity in a controlled setting.
The Defining Trait of the NOD Mouse
The defining feature of the NOD mouse is its spontaneous development of a condition similar to human Type 1 Diabetes (T1D). This occurs because the mouse’s immune system incorrectly identifies certain cells in the pancreas as foreign invaders. The targets of this assault are the beta cells, located in clusters known as the pancreatic islets. These beta cells are responsible for producing insulin, a hormone that regulates blood sugar levels.
The autoimmune attack on these cells is a process called insulitis, where immune cells infiltrate the islets. This infiltration leads to the gradual destruction of beta cells, causing a significant drop in pancreatic insulin content. The process begins early in the mouse’s life, with immune infiltration detectable as early as five weeks of age. As beta cell destruction progresses, the mouse loses its ability to produce sufficient insulin, resulting in hyperglycemia, or high blood sugar.
There is a pronounced difference in disease incidence between the sexes. Female NOD mice are far more susceptible to developing diabetes than their male counterparts. Studies have shown that by 30 weeks of age, approximately 86% of females will become diabetic, compared to only 48% of males. The onset of symptoms also occurs earlier in females, typically around 12 weeks of age, while males may not show signs for several more weeks.
Genetic and Immunological Basis
The tendency of NOD mice to develop autoimmunity is rooted in their genetic makeup. The strain is polygenic, meaning multiple genes contribute to its disease susceptibility. This complex genetic foundation results in several dysfunctions within the immune system, creating a predisposition for the body to fail in distinguishing its own cells from harmful pathogens.
A primary contributor to this immune dysregulation is found within the Major Histocompatibility Complex (MHC), a group of genes that code for proteins on the surface of cells that help the immune system recognize foreign substances. NOD mice possess an MHC haplotype, known as H2g7, which is inefficient at presenting self-antigens to developing immune cells. This deficit in antigen presentation is a reason the immune system fails to control T-lymphocytes that have the potential to react against the body’s own tissues.
This genetic framework leads to the survival and activation of autoreactive T-cells, which are immune cells that specifically recognize and target the body’s own proteins. In the case of NOD mice, these T-cells are directed against proteins found in the pancreatic beta cells, such as insulin. The immune system also has defects in other areas, including the function of natural killer (NK) cells and macrophage cytokine production, which further contribute to an imbalanced and overly aggressive immune response.
Role in Type 1 Diabetes Research
The NOD mouse’s predictable disease progression makes it a valuable tool for studying T1D. Researchers can observe the entire course of the disease, from the initial immune cell infiltration of the pancreas to the onset of hyperglycemia. This provides a window into the preclinical phase of T1D. By tracking these early stages, scientists can identify biomarkers that signal the start of the autoimmune attack long before symptoms emerge.
This model is used to test potential preventative therapies. Scientists can introduce various interventions, such as immunotherapies, to see if they can halt or slow the autoimmune process. For example, studies might involve administering agents designed to suppress the specific T-cells that attack beta cells or to promote regulatory immune cells that can quell the autoimmune response.
The NOD mouse also helps researchers investigate the environmental factors that may trigger or accelerate T1D. Studies can be designed to control variables like diet or exposure to specific viruses to understand how these external elements interact with genetic predispositions. This research is important for developing strategies that could one day reduce the incidence of T1D in at-risk human populations.
Beyond Diabetes: Other Research Applications
The immune system dysregulation in NOD mice makes them suitable for studying autoimmune conditions other than T1D. The same genetic susceptibilities that lead to the attack on the pancreas can manifest as autoimmune reactions against other tissues. This polyautoimmunity means the mice can spontaneously develop several other conditions, although often at a lower incidence than diabetes.
One example is Sjögren’s syndrome, an autoimmune disease characterized by immune system attacks on the glands that produce saliva and tears. NOD mice can develop autoimmune sialitis, an inflammation of the salivary glands that mirrors the human condition. Researchers use the model to explore the mechanisms behind this glandular destruction and to test therapies aimed at preserving gland function.
Genetic manipulation of the NOD strain has further broadened its research applications. By altering specific genes, scientists can create new mouse models that are resistant to diabetes but show a high incidence of other autoimmune diseases, like autoimmune thyroiditis. This demonstrates that the underlying autoimmune-prone genetic background can be shifted to target different organs. These variant strains have become tools for dissecting the specific pathways and genetic factors involved in a range of organ-specific autoimmune disorders.