Mast cells are immune cells that play a role in the inflammatory response against venom and parasitic infection, and are typically found in the skin, lungs, digestive system, and mucosal linings of the mouth and nose. Mast cells contain granules holding various chemical mediators, including tryptase, histamine, interleukins, and heparin. When activated, mast cells release the contents of these granules into surrounding tissue, causing swelling, flushing, itching and smooth muscle contraction as well as attracting other immune cells to the site and causing local inflammatory response.
Typically, mast cells are activated by specific antigens or antibodies to combat potential infections or parasites by recruiting additional immune cells. In various immunological conditions the mast cell response becomes dysregulated, leading to unwanted activation and symptomatic effects such as hives, itching, airway constriction, conjunctivitis or other inflammation. While mast cells can serve an important role in protecting against certain venoms and parasites, there is limited function or need for skin mast cells in modern settings.
Current therapeutic approaches to control mast cell responses include antihistamines, which counteract histamine release by activated mast cells, and anti-IgE antibody therapy, which aims to eliminate antibodies that trigger mast cell activation. Unfortunately, these approaches are ineffective for many patients, resulting in a continued high disease burden.
Mast cells in the skin, gut and lungs use a variety of cellular receptors and interactions with other cells to monitor and react to the local environment. The c-Kit receptor, and its ligand stem cell factor (SCF), is critical for mast cell development, proliferation and survival. Without continued signaling through the c-Kit receptor, mast cells will trigger orderly cell death (apoptosis).
Mast cells are among the longest-lived cells in the body and require substantial energy for the body to repopulate. Following depletion via c-Kit inhibition, it may take months or longer for mast cells to return to the skin.
Most current mast cell therapeutics under development target specific activation pathways such as MRGPRX2, FceR1 or IL-4R. Although these may be useful for subsets of patients, triggering mast cell depletion by blocking c-Kit receptor signaling may be a more potent and universal strategy for many immunological and inflammatory diseases with high unmet medical need.