Discovering epitope mimics (mimitopes) of chemical allergens that cause occupational asthma

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This high risk / high reward exploratory R21 project will make breakthroughs in understanding chemically-induced occupational allergy (asthma, hypersensitivity pneumonitis, skin disease). We will identify small molecules (peptides) that mimic the structure of chemical allergens by combining cutting edge technology with unique reagents generated in our laboratory. The results, including newly identified chemical allergen mimics (mimotopes), will lead to new diagnostics, surveillance approaches, and potential therapies. The immunology of chemical-induced occupational allergy has long remained unclear hindering the development of preventative, diagnostic and targeted therapeutic approaches. Chemical allergens are generally too small to trigger an immune response on their own but attain immunogenicity upon reacting with self-molecules. The specific structures (epitopes) of modified self proteins that trigger immune responses are challenging to define. While hapten-like recognition of chemicals (self-molecule conjugate) are possible, chemical allergens can also alter the native structure of self-molecules, creating new structures (neo-epitopes) recognized as foreign by the immune system. We hypothesize that peptide mimics of chemical allergens can be readily identified using contemporary phage-display libraries and bioinformatics with specific antibodies triggered by chemical exposure, either occupationally or in animal studies. We propose to define mimotopes of a model chemical allergen, methylene diphenyl diisocyanate (MDI), one of the most abundantly produced chemical allergens in the US. Mimotopes will be defined by combining SERA/IMUNE (a high-throughput bacteriophage-bioinformatic technology) with unique reagents from our laboratory (i) a panel of anti-MDI mAbs, (ii) IgE/IgA/IgG antibodies from mouse models of MDI asthma, and (iii) serum antibodies from MDI exposed/asthmatic workers. The biological relevance of newly identified mimotopes will be demonstrated through binding assays with serum samples from MDI exposed workers with and without asthma, animal models of MDI sensitization and asthma, and controls. Strong precedence for the proposed studies comes from published literature on mimotopes of chemical food contaminants, human autoimmune targets, and COVID-19 vaccine epitopes. The present investigation would bring similar cutting edge technology to the field of occupational chemical allergy that affects workers in multiple NORA sectors (Construction, Manufacturing, Transportation) and cross-sectors (Respiratory Health Immune, Infectious and Dermal Disease Prevention). r2P outputs and outcomes will be reduced hazardous exposures/immune disease via new diagnostics.