ENDOTOXIN AND ASTHMA PREVENTION IN YOUNG CHILDREN

本研究的主要目的是探讨慢性环境内毒素暴露在幼儿哮喘预防中的潜在作用。由于哮喘通常在儿童早期开始，在难治性疾病的典型病理性肺过程出现之前，减少哮喘炎症基础上的特应性免疫发育的干预和暴露可能对幼儿有最大的疗效。虽然在成人哮喘患者中，内毒素暴露已被证明是促炎和加重哮喘，但众所周知，它也是ifn - γ或“1型”免疫反应的有效诱导剂，这是对特应性“2型”免疫发育的反调节。因此，本建议的主要假设是，幼儿慢性内毒素暴露会通过增强1型免疫来预防哮喘，从而抑制特应性免疫发育和气道炎症。美国国立卫生研究院最近资助了一项名为“儿童哮喘预防研究”（CAPS）的研究，为以补充方式探索这一假设提供了一个绝佳的机会。CAPS是一项护士家访干预研究，它招募了180名市内至少有3次喘息发作的婴儿，并跟踪他们直到4岁，以了解哮喘的发展情况。补充CAPS的初步研究表明，在这些易患哮喘的婴儿中，室内灰尘内毒素水平的增加与过敏原致敏性的减少和1型免疫反应的增强有关。通过继续研究CAPS研究队列，我们建议确定慢性内毒素暴露是否通过增强1型免疫从而抑制过敏原致敏和2型免疫的发展，进一步降低6-7岁儿童哮喘的患病率。此外，还将研究导致内毒素免疫反应变化的几个因素。最终，这项研究可能有助于确定在生命早期增强1型免疫的潜力，作为哮喘和过敏的一级预防策略。新的诊断工具，以跟踪促哮喘免疫进展或解决已经开发，并将在此过程中进行测试。K23指导面向患者的研究职业发展奖将为儿童哮喘，过敏和免疫学专家候选人提供技能，经验，指导和知识，使其成为面向患者的研究中富有成效和独立的研究者。为了实现本奖项的目标，候选人已经设计了一份具体的研究职业发展计划，其中包括上述研究。

The primary objective of this research is to investigate the potential role of chronic environmental endotoxin exposure in asthma prevention in young children. Since asthma generally begins in early childhood, interventions and exposures that lessen the atopic immune development that underlies asthmatic inflammation may have their greatest efficacy in young children, prior to the advent of pathologic lung processes typical of the intractable disease state. Although endotoxin exposure has been shown, in adult asthmatics, to be pro-inflammatory and augment asthma, it is also well known to be a potent inducer of IFN-gamma or "Type 1" immune responses, that are counter-regulatory to atopic "Type 2" immune development. Therefore, the main hypothesis of this proposal is that chronic endotoxin exposure in young children will prevent asthma by enhancing Type 1 immunity, thereby inhibiting atopic immune development and airways inflammation. A recently funded NIH study, entitled the "Childhood Asthma Prevention Study" (CAPS), provides an outstanding opportunity to explore this hypothesis in a supplemental manner. CAPS is a nurse home visitation intervention study that is enrolling 180 Inner-city infants with at least 3 previous episodes of wheezing, and following them until age 4 years for the development of asthma. Pilot studies supplemental to CAPS have demonstrated that, in these asthma-prone infants, increased house dust endotoxin levels are associated with less allergen sensitization and enhanced Type 1 immune responses. By continuing to study this CAPS study cohort, we propose to determine if chronic endotoxin exposure further reduces the prevalence of asthma at ages 6-7 years, by enhancing Type 1 immunity and thereby inhibiting allergen sensitization and Type 2 immune development. As well, several factors contributing to variations in immune responses to endotoxin will be studied. Ultimately, this research may serve to define the potential of augmenting Type 1 immunity in early life as a primary prevention strategy for asthma and allergy. New diagnostic tools to follow pro-asthmatic immune progression or resolution have been developed and will be tested in the process. This K23 Mentored Patient-Oriented Research Career Development Award will provide the Candidate, a Pediatric Asthma, Allergy & Immunology specialist, with the skills, experience, mentorship, and knowledge needed to be a productive and independent investigator in patient-oriented research. A specific Research Career Development Plan has been designed by the Candidate that includes the research described above in order to accomplish the goals of this Award.