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

发现导致职业性哮喘的化学过敏原的模拟表位（模拟表位）

• 批准号: 10741979
• 负责人: ADAM WISNEWSKI
• 金额: $ 29.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741979
• 关键词: Discovering; epitope; mimics; mimitopes; chemical

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.

这个高风险/高回报的探索性R21项目将在认识上取得突破， 化学诱导的职业过敏（哮喘、过敏性肺炎、皮肤病）。我们将 识别小分子（肽），模拟化学过敏原的结构， 尖端技术与我们实验室生成的独特试剂。结果，包括 新发现的化学过敏原模拟物（mimotopes），将导致新的诊断，监测 方法和潜在的治疗方法。 化学物质诱发的职业性变态反应的免疫学机制长期以来一直不清楚 阻碍了预防、诊断和靶向治疗方法的发展。 化学过敏原通常太小，无法自行引发免疫反应， 免疫原性与自身分子反应。修饰自身的特定结构（表位） 触发免疫反应的蛋白质很难定义。虽然半抗原样识别 化学物质（自分子共轭）是可能的，化学过敏原也可以改变天然的 自我分子的结构，创造新的结构（新表位）被识别为外来的 免疫系统 我们假设化学过敏原的肽模拟物可以通过使用 当代噬菌体展示文库和生物信息学与特异性抗体触发 化学品暴露，无论是职业还是动物研究。我们建议定义一个 典型的化学过敏原，亚甲基二苯基二异氰酸酯（MDI），最丰富的 在美国生产化学过敏原。模拟表位将通过组合SERA/IMUNE（a）来定义。 高通量噬菌体-生物信息学技术）与我们实验室的独特试剂（i） 一组抗MDI mAb，（ii）来自MDI哮喘小鼠模型的IgE/伊加/IgG抗体，和（iii） MDI暴露/哮喘工人的血清抗体。新发现的生物相关性 模拟表位将通过与MDI暴露的血清样品的结合试验来证明。 有哮喘和无哮喘的工人，MDI致敏和哮喘的动物模型，以及对照组。 所提出的研究的强有力的优先权来自于已发表的关于以下模拟表位的文献： 化学食品污染物、人类自身免疫靶点和COVID-19疫苗表位。的 目前的调查将为职业化学品领域带来类似的尖端技术， 影响多个诺拉部门（建筑、制造、运输）工人的过敏 和跨部门（呼吸系统健康免疫、传染病和皮肤病预防）。R2p 产出和成果将是通过新的诊断方法减少危险接触/免疫疾病。