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Design of a Heterobivalent Inhibitor of Allergy and More Physiologically Relevant Allergy Models

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posted on 2013-04-02, 00:00 authored by Michael William Handlogten
One of the challenges in current therapies used to treat allergies is the non-specific suppression of the immune system which puts patients at increased risk for infections and development of cancers. This underlines the need to develop more specific treatments without the overall suppression of the immune system. This work demonstrates the proof of principle studies of a new approach that has the potential to respond to this need by selectively inhibiting mast cell degranulation. Specifically, heterobivalent inhibitors (HBI) were designed that simultaneously bound to two nearby sites located on the Fab domains of IgE antibodies?the antigen and nucleotide binding sites. These dual targeting HBIs had greater than 120 fold increased affinity for the target IgE compared to the monovalent hapten and prevented mast cell degranulation in a variant of the commonly used DNP/IgEDNP allergy model, however due to the many simplifications of this allergy model a more advanced heterotetravalent allergen (HtTA) model was developed. The HtTA allergy model allowed an integrative approach to study mast cell degranulation by presenting 2 haptens each with a valency of 2 and requiring both hapten specific IgEs to be present on the mast cell surface to stimulate degranulation. This model better reflected the polyclonal response observed in natural allergy systems and by chemically modifying the haptens, HtTAs that presented combinations of high and low affinity haptens were evaluated. Using this model we demonstrated the significance of low affinity epitopes and that selective inhibition of only the low affinity hapten, of an allergen made up of high and low affinity hatpens, was sufficient to prevent mast cell degranulation. The inhibition of mast cell degranulation observed in the in vitro rat basophilic leukemia mast cell model was used to define the parameters for the passive cutaneous anaphylaxis mouse model of allergy where similar stimulation and inhibition of allergy were observed, demonstrating the utility of the design. The described method of targeted inhibition has broad applications in inhibiting drug, food, and environmental allergies where the allergy epitopes are known and this study establishes a new practical use for the nucleotide binding site.

History

Date Modified

2017-06-05

Defense Date

2013-03-28

Research Director(s)

Basar Bilgicer

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Language

  • English

Alternate Identifier

etd-04022013-155410

Publisher

University of Notre Dame

Program Name

  • Chemical Engineering

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