IMMUNOPATHOGENESIS & PREVENTION OF ASTHMA IN YOUNG CHILDREN

我工作的研究基础是美国国立卫生研究院资助的一项前瞻性研究，该研究跟踪观察复发性喘息婴儿直到他们4岁。在我的导师Mary Klinnert博士（研究P.I.）和Donald Leung博士（主要导师）的指导下，180名哮喘易感婴儿的登记工作刚刚完成（见附件IRB性别/种族报告，1/26/00）。我们正在测量IgE， ECP和过敏皮肤测试作为特异反应的标志。作为GCRC建议工作的一部分，我还进行了详细的细胞研究，以确定产生促哮喘2型（IL-4, IL-5, IL-13）和反调节型1型（ifn -细胞因子）的不同淋巴细胞亚群（例如T-CD4+，记忆和幼稚；T-CD8+，记忆和幼稚）的比例。我寻求了解幼儿时期致病性Th2细胞的发育。这种性质的详细免疫分析可能最终用于预测可能发展为持续性哮喘的婴儿喘息。我最感兴趣的是我们研究中的一项新进展，表明幼儿慢性环境内毒素暴露（一种潜在的Th1通路诱导剂）可能具有特异保护作用。更具体地说，我们发现易患哮喘的婴儿对过敏原敏感，其屋尘内毒素水平明显较低，产生ifna的T淋巴细胞比例较低。该奖项第二年的进一步工作也揭示了：(1)室内灰尘中的内毒素可以诱导IFN-a的产生[AAAAI摘要，第一作者- Gereda JE（附）]；(2)所有年龄段的哮喘患者对内毒素的1型免疫反应都受损[AAAAI摘要，第一作者- Thatayatikom A.]。到目前为止，该工作的两篇手稿已提交发表。明年，我们将开始对4岁以上易患哮喘的婴儿进行最终评估。他们将被仔细评估哮喘、过敏原致敏和其他过敏性疾病的发展。我还计划对这些受试者进行1/ 2型免疫发育和内毒素反应性的免疫学评估，因为这与特应性的发展有关。

The research base for my work is a NIH-funded prospective study that follows recurrent wheezing infants until they are 4 years of age. With my mentors, Dr. Mary Klinnert (study P.I.) and Dr. Donald Leung (primary mentor), enrollment of 180 asthma-prone infants has just been completed (see attached IRB gender/ethnicity report, 1/26/00). We are measuring IgE, ECP, and allergy skin testing as markers of atopy. As part of the GCRC proposed work, I am also performing detailed cellular studies to determine the proportions of different lymphocyte subsets (e.g. T-CD4+, memory and naive; T-CD8+, memory and naive) that produce pro-asthmatic Type 2 (IL-4, IL-5, IL-13) and counter-regulatory Type 1 (IFN-cytokines. I seek an understanding of the development of the pathogenic Th2 cells during early childhood. Detailed immune profiling of this nature may ultimately serve to predict the infant wheezers who are likely to develop persistent asthma. I am most intrigued by a new development in our investigation, suggesting that chronic environmental endotoxin exposure ( a potential Th1 pathway inducer) in young children may have an atopy-protective effect. More specifically, we have found that asthma-prone infants who are allergen-sensitized have significantly lower levels of house dust endotoxin, and have lower proportions of IFNa-producing T lymphocytes. Further work in the second year of this award has also revealed that: (1) endotoxin in house dust can induce IFN-a production [AAAAI abstract, Primary author - Gereda JE (attached)]; and (2) asthmatics of all ages have impaired Type 1 immune responsiveness to endotoxin [AAAAI abstract, Primary author - Thatayatikom A. So far, two manuscripts of this work have been submitted for publication. Over the next year, we will begin final evaluations of asthma-prone infants who have now reached age 4 years. They will be evaluated carefully for the development of asthma, allergen sensitization, and other allergic diseases. I also plan to evaluate these subjects immunologically for Type 1/Type 2 immune development and endotoxin responsiveness, as this relates to the development of atopy.