Nanoparticles that target and deactivate mast cells prevented anaphylaxis in mice, Northwestern University researchers have found.
The research is in its early days. But in a proof-of-concept study, researchers designed nanoparticles that blocked the response of mast cells to allergens. During severe allergic reactions, mast cells release histamines and other inflammatory chemicals, and are a major contributor to anaphylaxis.
The key was coating the nanoparticles in two antibodies. One antibody is a “mock allergen” that binds to and activates mast cells, says Dr. Evan Scott. He’s the senior study author and a professor of biomedical engineering at Northwestern University in Chicago.
A second antibody, Siglec-6, does the opposite. When it binds to mast cells, it stops them from activating and releasing the chemicals involved in a reaction.
The researchers found that by engaging both types of receptors on the mast cells, the mice were protected against anaphylactic reactions. “Given these two contradictory signals, the mast cell decides that it shouldn’t activate and should leave that allergen alone,” Scott says.
Nanoparticles’ Promise
Nanoparticles are tiny particles, typically thousands of times smaller than a single cell. Nanoparticle excipients (the inactive ingredients that help drug delivery in the body) are already being used in some vaccines. These include the COVID-19 mRNA vaccines, and a few cancer medicines.
Yet, a lot of the excitement around nanoparticle research is the potential for targeted nanoparticles to deliver medications or other treatment to specific cells.
In food allergy, that could one day lead to nanoparticles that seek out and destroy only the mast cells that have antibodies to a particular allergen.
Mast Cells Remember Allergy
People with allergies produce IgE antibodies to their allergen, such as a food, when they eat it. Mast cells take up these antibodies, in effect, remembering them. Over time, if someone with a milk or a peanut allergy avoids their allergen, their levels of IgE circulating in the bloodstream fall. But mast cells remain ready to react to the allergenic protein as soon as its detected.
“The mast cells sit there with IgE antennae on their surface, waiting for the allergen to come along,” explains Dr. Bruce Bochner, study co-author and professor emeritus at Northwestern’s Feinberg School of Medicine.
Mast cells primed to react to a particular allergen represent only a small portion of the body’s total mast cells. In designing a treatment to protect from allergic reactions, you’d want the rest of the mast cells – the ones that don’t have the receptors to the allergen – to be left alone.
“You want that selectivity,” Scott says. “You want co-engagement of the receptors bound to the IgE antibodies that are specific to the allergen, and you want them to be shut down with the Siglec-6.”
Getting Antibodies to Stick
One technical challenge: biomedical engineers have struggled to get antibodies to stick to the surface of nanoparticles without altering the antibody’s structure or function. “Usually when antibodies stick to nanoparticles, the antibodies get bent out of shape and they don’t always work so well,” Bochner says.
Scott and his team overcame that in the study, published in Nature Nanotechnology. Using a new technique, they coated nanoparticles with antibodies while keeping them intact. They also precisely controlled the concentration of antibodies on the surface.
That matters. Too much of one antibody or too little of the other could cause an anaphylactic reaction, Scott explains.
“We had to figure out how much of this one? How much of that one?” Scott says. Using mast cell cultures from human skin samples in the lab, they found the “sweet spot of antibodies to shut down the mast cell.”
Experiments in Mice
Next came experiments in mice specially bred to produce human mast cells. (In earlier research, Bochner had discovered that Siglec-6 is only found on human mast cells.)
When the mice received infusions of the nanoparticles coated only in the mock allergen antibody, they experienced anaphylaxis, as expected. The researchers also tried giving the mice the antibodies without using the nanoparticles. Again, the mice showed symptoms of anaphylaxis.
Only when mice received the nanoparticles coated with both antibodies did they show no signs of an allergic reaction. “The only way you get inhibition is if you put both types of antibody … together on the same nanoparticle,” Bochner says.
In one final experiment, mice sensitized to an IgE allergen were given the nanoparticle infusions with the two antibodies, and exposed to their allergen. None experienced signs of an allergic reaction.
Nanoparticles and Allergies
By using the mock allergen antibody, the research demonstrates that the Northwestern team’s approach could work with any allergen, Bochner explains.
The mock allergen antibody binds with the same receptors on mast cells that IgE antibodies bind with. Future research will try the technique with nanoparticles coated in peanut protein or other allergens along with Siglec-6.
It’s possible that nanoparticle injections or infusions could one day be used for short-term protection from allergic reactions. For instance, if someone with an allergy to a medication needed to take it and there wasn’t an alternative. “Could you pre-treat them with this for a short-term indication?” Bochner says.
Or, nanoparticles could be coated in the antibodies and loaded with a drug that would kill only the allergy-specific mast cells.
There is still much that needs to be learned, Bochner says. This includes how long the nanoparticles remain in the body and how long protection against allergic reactions lasts. As well, mast cells play a role in immune function. So researchers need to find out more about how any treatment would impact mast cells in general, not just those that are allergy-specific.
Exciting Progress, But Many Questions
Plus, mast cells are continually being produced. Even if you inactivated or killed some, when you ate the allergenic food again, you would then produce more IgE. Would this in turn ready the new mast cells to react? “It would likely need to be some sort of repetitive administration over time,” Bochner says.
However, the progress, and the possibilities, are exciting. “The long-term goal of nanoparticles is to be able to selectively deliver a treatment that is cell-type specific,” Bochner says.
What researchers are learning is that “sometimes you need to present two signals to the cells, in a really clustered way, to get the outcome you’re after.” With this new nanoparticle, they now have a method of doing that, and the Siglec-6 target to go after.
Social share image: a schematic illustration of the nanoparticle covered in the 2 antibodies. Credit: Evan A. Scott / Northwestern University
Related Reading:
Xolair for Food Allergies: the Study Results That Led to FDA Approval
Pill That Treats Cancer Prevented Food Allergy Reactions
