A Murine Model of Inflammation Based on Chronic Expression of Interferon-Gamma

An autoimmune disease is characterized by a malfunctioning healthy immune system mistakenly attacking healthy cells, tissues, and organs. These chronic diseases likely result from interactions between genetic and environmental factors. Gender, race, and ethnicity characteristics have been linked to the development of an autoimmune disease. Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. Importantly, autoimmunity is known to have a genetic basis and tends to cluster in families.

The cytokine Interferon gamma (IFNγ) is critical for innate and adaptive immune responses. Aberrant expression of this pro-inflammatory factor is linked to several autoimmune and autoinflammatory diseases. Its importance in the immune system stems from its immunostimulatory and immunomodulatory effects and the ability to inhibit viral replication directly. IFNγ is also essential many immunotherapies to be successful. Several instances of signaling modulation seem particularly applicable to autoimmune inflammation.

The lab of Dr. Howard Young at NCI’s Laboratory of Cancer Immunometabolism developed an ARE-Del mouse model for studying female-biased autoimmune diseases. By replacing the sequence that enhances IFNγ mRNA degradation (AU Rich Elements) with random nucleotides, these mice produce stable IFNγ mRNA in T-cells and NK cells and chronic protein expression in the serum. This model enables both short- and long-term assessment of the effects of IFNγ on host tissue and mouse behavior. Serum IFNγ was elevated at baseline in Systemic Lupus Erythematosus (SLE) patients prior to therapy – consistent with observations in the mouse. The Young lab observed immunoglobulin deposition in the kidney with a female bias in the mice, consistent with lupus.

In addition to SLE, the Young lab has shown this model can be used to study both Primary Biliary Cholagitis (PBC) and Premature Ovarian Failure (POF). PBC is a disease that is nine times more likely to affect females and leads to cirrhosis and liver failure, occuring in about 10% of women over the age of forty. Histological data from these mice show portal inflammation, lobular inflammation, bile duct damage, and granuloma formation – identical to what is observed inPBC patients. 

In autoimmune Primary Ovarian Failure, ovarian damage is caused primarily by T-cell (CD8+) mediated injury. The precise mechanisms of POF development are currently unknown, and existing animal models lack some clinical features. The ARE-Del model has been shown to have the characteristic features of autoimmune POF.

In summary, the Young lab developed a mouse model of autoimmunity that mimics multiple autoimmune diseases due to chronic IFNγ expression. This mouse offers an in vivo model for developing new therapies that can control or reverse disease phenotype. The NCI is actively seeking parties interested in licensing this autoimmune disease model. 

Competitive Advantages:

• Presents characteristic features of Systemic Lupus Erythematosus, Primary Biliary Cholagitis, and Premature Ovarian Failure
• Mouse model can be used to develop licensee’s own pipeline

Commercial Applications:

• Novel model for female-biased autoimmune diseases, including:
  • Systemic Lupus Erythematosus
• Primary Biliary Cholagitis
• Premature Ovarian Failure
• In vivo model for developing new