The central role of IgG4 underlying much of the clinical response to allergen immunotherapy via allergen neutralization has been strengthened by a study of passively immunizing patients with cat allergy with monoclonal anti–Felinus domesticus 1 (Fel d 1) IgG4, which has induced rapid clinical benefit in cat dander challenge studies.
Neutralizing Fel d 1 with passive immunization by using anti–Fel d 1 antibody is thus a potential therapeutic for patients with cat dander allergy.
The same researchers observed that cat salivary concentrations of Fel d 1 dropped over a relatively similar time course.
Cat health was seemingly unaffected by the IgY; it is believed that Fel d 1 has a dispensable biologic role.
A pilot crossover double-blinded chamber exposure challenge found that subjective throat and nose symptom scores improved significantly, and subgroup analysis found that nasal congestion was significantly improved.
The unique characteristics of IgY
The closest extant homolog isotype of mammalian IgG, namely, avian IgY, seems to violate multiple canonic immunology precepts. For example, because gastric acid and enzymatic hydrolysis prevent consideration of orally administered IgG, how IgY escapes destruction in the gut is perplexing. Additionally, conventional wisdom is challenged by how IgY is enterically absorbed, escapes immunologic destruction, and can then be excreted intact across mammalian mucus membranes.
The origin of IgY still remains ambiguous, but IgY is widely believed to be the progenitor of both IgG and IgE isotypes.
Significant differences in the generation of hypervariable regions also exist: the primary mechanism by which IgY generates diversity is via pseudogenes, which are nonfunctional DNA fragments resembling functional genes, rather than via V(D)J recombination.
IgY as a therapeutic
As such, adoptive transfer of IgY to humans appears to possess highly restricted immunologic activity compared with that of mammalian IgG, perhaps accounting for the limited toxicity, off-target inflammatory injury, and negligible adverse events in clinical studies to date. Clinically relevant human anti-IgY neutralizing antibodies, IgE anti-IgY antibodies, and serum sickness appear curiously rare in clinical and animal studies.
As egg protein powder is already classified as generally recognized as safe by the US Food and Drug Administration, hyperimmune IgY dietary supplements already bypass many regulatory hurdles.
To date, human use of polyclonal IgY therapeutically remains limited to early-phase clinical studies, orphan drug approvals, and unregulated dietary supplements.
Hyperimmune polyclonal IgY appears to offer multiple affordances over IgG-based therapeutics, yet it has suffered widely from insufficient scientific inquiry. With regard to this novel proposed clinical utilization of polyclonal IgY for allergic rhinitis, more robust validation of the molecular neutralization of Fel d 1 allergenicity and clinical efficacy is first necessary. IgY binding and valency to relevant Fel d 1 linear and conformational allergenic epitopes would benefit from affirmation via high-molecular-weight mass spectroscopy, Western blot, or pull-down assays. Dose-effect comparisons of neutralized Fel d 1 with untreated Fel d 1 could be determined via basophil activation tests in vitro and double-blinded direct nasal provocation challenges with sensitized patients. Akin to the robust studies that our specialty has performed with dust mite and pest antigen reduction interventions, real-world, in-home effectiveness studies using relevant clinical outcomes would be needed before implementation of hyperimmune IgY-treated cat food as a unique and fascinating new tool for clinical management.
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Published online: September 13, 2021
Received in revised form:
In Press Journal Pre-Proof
Supported with institutional funding from the Medical College of Wisconsin .
Disclosure of potential conflict of interest: The author declares that he has no relevant conflicts of interest.
© 2021 American Academy of Allergy, Asthma & Immunology