How desensitization works, and how it could lead to better allergy therapy

Scientists have long understood that rush desensitization therapy somehow disrupts mast cells through the repeated exposure of allergens in quick succession and increasing doses. But the mechanism that underlies this technique has never been identified, until now.

In a study published online September 26, 2016 in the Journal of Clinical Investigation, researchers showed that rush desensitization disrupts actin—a protein that forms tiny filaments within mast cells. And it’s the disruption of actin that disables mast cells from producing the calcium response necessary for their degranulation, and ultimately quells the allergic reaction.

“We have known for at least 100 years that the [desensitization] approach is effective,” said senior author Soman Abraham, PhD, Professor in the Departments of Pathology, Immunology, and Microbiology and Molecular Genetics at Duke University School of Medicine, in Durham, NC. “People who have terrible, even life-threatening reactions to certain antigens can then tolerate an exposure—if just for a short period of time.”

Earlier research had suggested that rush desensitization works because it incites mast cells and basophils to internalize IgE, thus preventing degranulation as well as any further responses to the allergen.

But the findings from the current study demonstrated a decidedly different mechanism. First, in both in vivo and in vitro models, the researchers found that even desensitized mast cells could still bind to the allergen after desensitization, which suggested that enough IgE remained on the surface of the mast cells to produce degranulation. Thus, something other than IgE must be involved.

Instead, the research findings indicated that the desensitized mast cells lacked the usual calcium response that provokes (at least in part) both degranulation and cytokine production. And, the process of rush desensitization—exposing mast cells to frequent and increasing amounts of allergen—resulted in the significant redistribution of actin.

Normally, when mast cells are challenged by an allergen, the actin breaks down and redistributes into small aggregates dispersed throughout the cell in preparation for discharging granules and releasing inflammatory mediators.

But after rush desensitization, the researchers observed that actin was markedly reorganized, and largely failed to release granules even after 2 hours. This reorganization of actin appeared to avert the calcium response thereby preventing the allergic reaction, the researchers noted.

However, desensitization and the lack of an allergic reaction last only for a short time.

“Having figured out the mechanism, we should now be able to find new drugs that can target the actin and prolong the desensitization,” said lead author Weixin Gladys Ang, a PhD candidate in the Molecular Genetics and Microbiology Department at Duke. “This will allow for recovery to be slower, enabling people to be tolerant of allergens for longer periods.”