Scientists at Duke-NUS Medical School have figured out the initial step in the process when someone comes into contact with an allergen, like peanuts, shellfish, pollen or dust mites. This breakthrough could lead to the creation of medications to stop these severe reactions. Their findings were published in the April edition of Nature Immunology.Mast cells, a type of immune cell, can mistakenly identify harmless substances like peanuts or dust mites as threats, causing them to release a rapid first wave of bioactive chemicals in response. These mast cells are located in the skin, around blood vessels, and in the linings of the airways and gastrointestinal tract. When they all release their stored chemicals into the bloodstream at the same time, it can lead to immediate and systemic shock, which can be life-threatening without prompt intervention.
According to the World Health Organization (WHO), more than 10% of the global population suffers from food allergies. Allergy rates are on the rise, with an increase of 50% in children over the past 20 years.As asthma and food-triggered anaphylaxis cases increase globally, the incidence of these conditions in Singapore is also on the rise. One in five children in Singapore suffers from asthma, and food allergies are currently the primary cause of anaphylactic shock.
Researchers at Duke-NUS have made a breakthrough discovery regarding the release of mast cell granules that contain bioactive chemicals. This release is regulated by two members of an intracellular multiprotein complex known as inflammasome. Previously, these inflammasome proteins were thought to only spontaneously assemble in immune cells to release soluble chemicals that alert other parts of the immune system when a threat is detected.The research, led by Professor Soman Abraham, found that the components of the inflammasome play a crucial role in transporting mast cell granules from the cell centre to the cell surface, where they are released. This discovery provides a specific target for intervention to prevent the cascade of events that lead to anaphylactic shock.The discovery was made while studying mice with mast cells that were missing either NLRP3 or ASC, two proteins involved in the inflammasome. When these mice were exposed to allergens, they did not experience anaphylactic shock. However, when the mast cell NLRP3 and ASC proteins came together and attached to individual granules inside the cell, it formed a complex called granulosome. This complex helped the granules move along tracks formed by the cytoskeleton within the mast cell, similar to hooking them onto a set of “rail tracks.” Dr. Pradeep Bist, a principal research scientist with Duke-NUS’ Emerg, and co-first author of the paper, explained the findings.The head of the Infectious Diseases Programme explained that when mast cells are activated, there is a rapid movement of granules along microtubules to the cell membrane, where they are then released from the cell. However, when mast cells are deficient in NLRP3 or ASC proteins, there is no movement of granules within the cell and none of them are released. After demonstrating the role of NLRP3 and ASC in this process, the team tested known inflammasome inhibitors to see if they could prevent this event from happening. They used an inflammasome-blocking agent to carry out their experiments.The drug, known as CY-09, is similar to those being tested for chronic inflammatory diseases in clinical trials. Researchers gave this therapy to mice before exposing them to an allergen and found that it effectively prevented anaphylactic shock in their preclinical model.
Dr. Andrea Mencarelli, from the Shanghai Jiao Tong University School of Medicine’s Immune Therapy Institute in Shanghai, China, and a co-author of the paper, noted that using a drug that specifically blocked inflammasome protein activity was able to achieve these results.to selectively block the release of mast cells’ pre-stored chemicals without affecting other potentially beneficial activities of mast cells.”
While not a cure, this could provide individuals with severe allergies a new method to prevent the onset of a potentially traumatic reaction. Emergency treatments are currently taken immediately after the first symptoms appear. These treatments must be given within a short period of time to be effective and they also come with serious side effects.
“I could see this providing relief to parents of children with severe food allergies.This provides short-term protection in situations where the exposure risk is uncertain. We are working on optimizing the dosage and frequency of the drug for the best protective effects against anaphylactic shock,” explained Prof Abraham. “After this, we aim to do the same for asthma and allergic skin reactions.”
Prof Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented, “This breakthrough has great potential for translation and represents a significant step forward in the field.This represents a significant shift in the way we approach further research, but more importantly, it has the potential to improve the quality of life for those who are at risk of severe allergic reactions. This discovery is particularly hopeful for parents of young children who are constantly worried about their child’s well-being.”
The study was carried out in accordance with the National Advisory Committee for Laboratory Animal Research (NACLAR) guidelines.
