IMMUNOPATHOGENESIS & PREVENTION OF ASTHMA IN YOUNG CHILDREN

我工作的研究基础是由美国国立卫生研究院资助的一项前瞻性研究，该研究跟踪观察反复喘息的婴儿，直到他们4岁。和我的导师玛丽·克林纳特博士(研究P.I.)与首席导师唐纳德·梁博士一起，180名哮喘易感婴儿的登记工作刚刚完成(见所附的IRB性别/种族报告，1/26/00)。我们正在测量IgE、ECP和过敏性皮肤测试作为特应性反应的标志。作为GCRC拟议工作的一部分，我还在进行详细的细胞研究，以确定不同淋巴细胞亚群(例如T-CD4+、Memory和NAIVE；T-CD8+、Memory和Naive)产生哮喘前2型(IL-4、IL-5、IL-13)和反调节1型(干扰素-细胞因子)的比例。我想了解儿童早期致病Th2细胞的发育情况。这种性质的详细免疫图谱最终可能有助于预测可能发展为持续性哮喘的婴儿喘息者。我最感兴趣的是我们研究中的一项新进展，表明幼儿长期暴露于环境内毒素(一种潜在的Th1途径诱导物)可能具有特应性保护作用。更具体地说，我们发现过敏原致敏的哮喘易感婴儿的室内粉尘内毒素水平显著较低，产生IFNA的T淋巴细胞比例也较低。该奖项第二年的进一步工作还揭示了：(1)室内灰尘中的内毒素可以诱导干扰素-α的产生[AAAAI摘要，主要作者-Gereda je(附件)]；以及(2)所有年龄的哮喘患者都损害了对内毒素的1型免疫反应[AAAAI摘要，主要作者-Thatayatikom A.到目前为止，这项工作的两篇手稿已提交发表。在接下来的一年里，我们将开始对现在已满4岁的易患哮喘的婴儿进行最终评估。将仔细评估它们是否会发展为哮喘、过敏原过敏和其他过敏性疾病。我还计划对这些受试者进行免疫学评估，以了解1型/2型免疫发展和内毒素反应性，因为这与特应性疾病的发展有关。

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.