IMMUNOPATHOGENESIS & PREVENTION OF ASTHMA IN YOUNG CHILDREN

我工作的研究基础是NIH资助的一项前瞻性研究，该研究跟踪了反复喘息的婴儿，直到他们4岁。与我的导师，博士玛丽Klinnert（研究P.I.）和Donald Leung医生（主要导师），刚刚完成了180例哮喘易感婴儿的入组（见随附的IRB性别/种族报告，2000年1月26日）。我们正在测量作为特应性标志物的IgE、ECP和过敏皮肤测试。作为GCRC拟议工作的一部分，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1型（IFN-细胞因子）的不同淋巴细胞亚群（例如T-CD 4+，记忆和幼稚; T-CD 8+，记忆和幼稚）的比例。我寻求了解儿童早期致病性Th 2细胞的发展。这种性质的详细免疫分析可能最终有助于预测婴儿喘息谁可能发展为持续性哮喘。我最感兴趣的是在我们的调查中的一个新的发展，这表明，慢性环境内毒素暴露（一个潜在的Th 1通路诱导剂）在幼儿可能有过敏性保护作用。更具体地说，我们发现过敏原致敏的哮喘易感婴儿的室内灰尘内毒素水平明显较低，产生IFN α的T淋巴细胞比例较低。该奖项第二年的进一步研究还表明：（1）室内灰尘中的内毒素可诱导IFN-α产生[AAAAI摘要，第一作者- Gereda JE（随附）];和（2）所有年龄段的哮喘患者对内毒素的1型免疫应答受损[AAAAI摘要，第一作者- Thatayatikom A. 到目前为止，这部作品的两份手稿已提交出版。在接下来的一年里，我们将开始对4岁以上有哮喘倾向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的1型/2型免疫发育和内毒素反应性进行免疫学评价，因为这与特应性的发生有关。

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.