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Novel peanut-specific human monoclonal IgE antibodies could open up new therapeutic targets for peanut allergies
It is estimated that approximately 10% of the U.S. population suffers from peanut allergy, a medical emergency that can be treated but not cured. Compared to people without allergies, these people are at higher risk of anaphylaxis. Therefore, there is a need to develop novel therapies to treat peanut and other food allergies. A recent Frontiers in Immunology journal study conducted by researchers at the University of North Carolina at Chapel Hill and Vanderbilt University developed an in vitro system to determine potential therapeutics targeting sensitized effector cells based on human, allergen-specific monoclonal immunoglobulin E (IgE) antibodies (mAbs). Study: ...
Novel peanut-specific human monoclonal IgE antibodies could open up new therapeutic targets for peanut allergies
It is estimated that approximately 10% of the U.S. population suffers from peanut allergy, a medical emergency that can be treated but not cured. Compared to people without allergies, these people are at higher risk of anaphylaxis. Therefore, there is a need to develop novel therapies to treat peanut and other food allergies. A recent one Frontiers in immunology A journal study conducted by researchers at the University of North Carolina at Chapel Hill and Vanderbilt University developed an in vitro system to determine potential therapeutics targeting sensitized effector cells based on human allergen-specific immunoglobulin E (IgE) monoclonal antibodies (mAbs).
How does an allergic reaction occur?
Allergic reactions are mainly triggered by mast cells (MCs). During the allergy effector phase, mast cells are activated by the cross-linking between allergenic antigens and allergen-specific immunoglobulin (Ig)E, which binds to the IgE receptor (FcϵRI) on MCs. The activated MCs promote allergic symptoms by degranulating and releasing previously formed mediators.
Preformed mediators such as vasoactive amines, the cytokine tumor necrosis factor (TNF)-alpha, and proteases are stored in MC cytoplasmic granules. Interestingly, MCs also synthesize additional cytokines and de novo lipid mediators to maintain allergic symptoms. Therefore, new treatments for food allergy could be developed that target MC activity during the allergy effector phase.
Based on a mouse model of allergic peritonitis and passive cutaneous anaphylaxis models, MC inhibitory receptors, such as sialic acid-binding immunoglobulin-like lectin (Siglec)-8 and CD300a, attenuate allergic inflammation and MC degranulation.
Models for identifying therapeutic targets to inhibit food allergic reactions
Antigen-specific, IgE-mediated MC activation was inhibited in vitro by nanoparticles that simultaneously presented antigen and Siglec-8 ligands. In addition, it could also suppress anaphylaxis in Siglec-8 transgenic mouse models. Although few studies have determined the effect of inhibiting MCs sensitive to the food allergen, egg ovalbumin (OVA), researchers have not yet determined whether targeting CD300a or Siglec-8 affects in vitro MC activation in response to peanut.
Several in vitro models of the allergy effector phase have been developed based on purified human IgE antibodies. These models showed that anti-human IgE antibodies always cross-linked IgE-FcεRI complexes on the MC and triggered degranulation. However, this was not the case for MCs sensitized to human sera with anti-food allergen IgE. In this case, degranulation did not always occur in the presence of specific food allergens.
About 30% of patients with food allergies are allergic to more than one food. Therefore, models that used human plasma to sensitize MCs face reproducibility issues due to variability in IgE levels and IgE specificity to multiple allergens. Therefore, alternative in vitro models of food allergen-induced MC degranulation are needed to determine MC inhibitory receptors and evaluate the effect of potential therapeutics that can target these inhibitory receptors.
Development of potential therapeutics for peanut allergy
A novel in vitro system was developed to mimic the effector phase of peanut allergy by using naturally occurring peanut-specific human IgE monoclonal antibodies (mAbs) to sensitize an established effector cell line.
Two new human peanut-specific IgE mAbs were generated using human hybridoma techniques used to sensitize rat basophilic leukemia (RBL) SX-38 cells expressing the human IgE receptor (FcϵRI). These peanut-specific human IgE mAbs could be directly cross-linked to the clinically relevant food allergen peanut, reproducibly causing activation and degranulation of allergic effector cells.
After stimulation with peanuts, cytokine production, beta-hexosaminidase release (degranulation markers), and phosphorylation of signal transduction proteins downstream of FcϵRI were measured. The extent of degranulation was also estimated after activation of the inhibitory receptors CD300a and Siglec-8.
Previous studies have suggested inhibitory mast cell surface receptors with an immunoreceptor tyrosine-based inhibition motif (ITIM) as possible pharmaceutical targets that can inhibit degranulation and MC activation in food allergy. Here, scientists examined the effect of monoclonal antibodies specific for CD300a and Siglec-8 receptors on allergic effector cells sensitized with peanut-specific IgE.
The results associated with Siglec-8 supported the proof of concept associated with the observation of an in vitro system that discovered inhibitors of MC degranulation. In particular, the CD300 receptor family was found to represent a potential therapeutic target for blocking the activation and degranulation of peanut-specific allergic effector cells.
The underlying mechanism of Siglec-8-mediated inhibition of MC has been linked to direct interactions between Siglec-8 and signaling molecules downstream of FcϵRI.
In the future, scientists can use this in vitro model to determine whether phosphatases are linked to CD300a and Siglec-8 signaling in the RBL-SX-38 effector cell line. The main advantage of the new model is that it allows direct detection of potential therapeutics upon effector cell activation by eliminating variables encountered when using human plasma for sensitization. In addition, this system removes irrelevant IgE, multiclonal allergen-specific IgE and other irrelevant antibody subclasses, which is advantageous as it allows rapid screening for potential candidates for effector cell inhibition in food allergy.
Reference:
- Suber, J. et al. (2022) Neuartige erdnussspezifische monoklonale humane IgE-Antikörper ermöglichen Screenings auf Inhibitoren der Effektorphase bei Nahrungsmittelallergien. Grenzen in der Immunologie. https://doi.org/10.3389/fimmu.2022.974374, https://www.frontiersin.org/articles/10.3389/fimmu.2022.974374/full