Environmental Factors – February 2023: Why Immunotherapy for Peanut Allergy Works for Some, Not All

Thanks to Jeffrey Mueller, PhD, Director of the NIEHS Nuclear Magnetic Resonance Research Core Facility, and collaborators at Massachusetts General Hospital (MGH) and Paris Saclay University.

Read more about Mueller and his groundbreaking work in visualizing the molecular structure of allergens in this June 2022 Environmental Factors article. (Photo courtesy of Steve McCaw/NIEHS)

A structural biology approach called X-ray crystallography has revealed why oral immunotherapy to treat food allergies with increased consumption of the allergen can lead to lasting tolerance in some people but only transient tolerance in others.

The new research findings, which are published in the Journal of Clinical Research, may help researchers improve allergy treatments so that all patients can benefit.

Therapies are not one-size-fits-all

Food allergies are caused by IgE antibodies that are produced by the immune system and bind to allergens such as peanuts, triggering a reaction that can be potentially life-threatening in extreme cases.

Ingestion of allergens through oral immunotherapy as a treatment for food allergy increases blood levels of allergen-specific IgG neutralizing antibodies that prevent IgE-mediated allergic reactions. However, only a subset of people with peanut allergy develop sustained responses to oral immunotherapy.

“We hypothesized that in people with long-term tolerance after peanut oral immunotherapy, allergen-specific protective antibodies may have unique properties—for example, how well they recognize the allergen—that may result in their ability to effectively neutralize the allergen. And thus lead to tolerance. ,” senior writer Sarita Yu. Patil, MD said

Why some but not others?

Blood collected from pediatric and adult participants in two peanut oral immunotherapy clinical trials at MGH was analyzed, and then the researchers applied a fluorescence-based method previously developed by Patil to identify cells in the blood that make antibodies against peanut allergens.

The team found that neutralizing antibodies from patients with permanent tolerance after immunotherapy blocked specific regions of the peanut allergen, thereby disrupting the binding ability of IgE antibodies. Antibodies from patients with only transient tolerance after immunotherapy did not block these regions.

Seeing is believing

A team of researchers at NIEHS, led by Jeffrey Mueller, Ph.D., was able to specifically identify these important areas.

“We were able to use X-ray crystallography to see the first complex structures that describe how human antibodies interact with peanut allergens,” Muller said. “After studying allergens for so many years, this was a very gratifying and important new development.”

According to Patil, the research is the first to identify tools to identify neutralizing antibodies in allergens, describe their mechanisms, and evaluate their effectiveness in preventing allergen IgE antibodies from binding to allergens.

“This provides a new avenue for both therapeutic and diagnostic test development,” Patil said. “Therapeutically, neutralizing antibodies may be able to provide clinical protection. From a diagnostic standpoint, we may be able to predict future tolerance development based on the presence or absence of these antibodies in patients.”

Quote: LaHood NA, Min J, Keswani T, Richardson CM, Amoako K, Zhou J, Marini-Rapoport O, Bernard H, Hazebrouck S, Shreffler WG, Love JC, Pomes A, Pedersen LC, Mueller GA, Patil SU. 2023. Immunotherapy-induced neutralizing antibodies disrupt allergen binding and maintain allergen tolerance in peanut allergy. J Clin Invest. 133(2):e164501.

(This article is based on a press release by Noah Brown, Massachusetts General Hospital.)

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