W32 - Therapeutic Effects of Anti-IFNg Therapy in a Spontaneous Mouse Model of Myositis

Myositis are autoimmune and inflammatory disorders leading to skeletal muscle weakness and disability. Human studies suggest a role for type I and II interferons in the pathogenesis of the disease. Few clinical trials used anti-IFNg blocking antibodies in autoimmune conditions such as Crohn’s disease (HuZAF), systemic Juvenile Idiopathic Arthritis and Adult-onset Still's Disease (Emapalumab), but their therapeutic relevance in myositis has not been studied.

The scarcity of myositis murine models has been a roadblock in therapeutic research. ICOS signaling pathway invalidation on the diabetes-prone NOD mouse background switches their phenotype from spontaneous diabetes to myositis. Icos^-/- NOD mice display reduced muscle strength and impaired locomotor activity but no diabetes. Muscles exhibit extensive immune cell infiltration with abundant macrophages and TCD4 cells. Molecular analyses revealed myofiber mitochondrial abnormalities, ROS production and extensive oxidative stress. We found that IFNg and IFNg-induced (Cxcl9, Cxcl10, Gbp2) gene expressions were significantly elevated in muscles from these mice with established myopathy, which led us to evaluate the therapeutic potential of IFNg blockade. Anti-IFNg administration strikingly haltered myositis clinical progression, with reduced muscle strength loss and preservation of normal locomotor activity (Catwalk gait analysis). Moreover, anti-IFNg significantly reduced chemokine expression, immune cell infiltration and free radical production. Ex vivo peripheral immune cell restimulation showed that Th1/Th2/Th17 profiles were not altered by the treatment. This may suggest that anti-IFNg therapy blocked effector mechanisms rather than on T cell priming.

This work supports the relevance of IFNg in the pathogenesis of myopathy and demonstrate the relevance of IFNg-blocking antibodies.