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.
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