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。由于哮喘通常始于儿童早期，因此在出现典型的难治性疾病状态的病理性肺部过程之前，减轻哮喘炎症基础的特应性免疫发育的干预和暴露可能在幼儿中具有最大的疗效。尽管在成人哮喘患者中，内毒素暴露已显示为促炎性的并增强哮喘，但也众所周知它是IFN-γ或“1型”免疫应答的有效诱导剂，其对特应性“2型”免疫发育起反调节作用。因此，该建议的主要假设是，幼儿的慢性内毒素暴露将通过增强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。最近由美国国立卫生研究院资助的一项名为“儿童哮喘预防研究”（CAPS）的研究为以补充的方式探索这一假说提供了一个极好的机会。CAPS是一项护士之家访问干预研究，招募了180名至少有3次喘息发作的城市婴儿，并跟踪他们直到4岁的哮喘发展。补充CAPS的初步研究表明，在这些哮喘易感婴儿中，室内灰尘内毒素水平升高与过敏原致敏性降低和1型免疫应答增强相关。通过继续研究该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型免疫力从而抑制过敏原致敏和2型免疫发育来进一步降低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型免疫力作为哮喘和过敏的一级预防策略的潜力。已经开发了新的诊断工具来跟踪促哮喘免疫进展或消退，并将在此过程中进行测试。这个K23指导的以患者为导向的研究职业发展奖将为候选人，儿科哮喘，过敏和免疫学专家，提供成为以患者为导向的研究中富有成效和独立的研究者所需的技能，经验，指导和知识。候选人设计了一个具体的研究职业发展计划，其中包括上述研究，以实现该奖项的目标。

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.