Perinatal Antigen Exposure and Allergic Asthma

该项目的总体目标是确定围产期抗原暴露对哮喘小鼠模型过敏性呼吸道炎症发展的影响。流行病学研究表明，有哮喘家族史的儿童患哮喘的风险增加。特别是，新生儿的过敏反应与母亲的过敏密切相关，而与父亲的过敏无关。因此，我们认为，在围产期接触抗原的时机和途径(例如，经胎盘、出生后通过母乳口服或出生后吸入)对免疫反应具有终生影响，可能包括提高敏感性或耐受性。然而，负责的细胞以及它们决定新生儿对呼吸道敏感性或耐受性的功能性承诺的机制仍有待确定。我们将探索围产期暴露于模型蛋白抗原卵清蛋白(OVA)如何影响T细胞和B细胞免疫反应性的发展。特别是，由于已知在妊娠期间存在T细胞发育的有序波，携带含有伽马链和增量链的T细胞受体(TCR)的T细胞首先出现，我们将确定这些细胞的存在或不存在如何影响随后的抗OVA反应的数量和质量。围产期暴露于OVA的后果将通过比较免疫(系统免疫)和气溶胶攻击(呼吸道炎症反应)期间抗原特异性CD4+TCRAlphabeta细胞和B细胞的数量和功能特性来评估已达到6-8wk年龄的小鼠。因此，我们特别提出：目的1.确定围产期双亲与环境来源的OVA暴露对子代免疫反应发展的影响。目的2.确定母体(或父体)对OVA(致敏和耐受)的免疫应答能力，以调节其后代对同种或异种抗原的免疫。目的3.鉴定围产期培养的将致敏或保护传递给幼龄小鼠的白细胞群体。

The overall goal of this project is to determine the impact of perinatal antigen exposure on the development of allergic airway inflammation in a murine model of asthma. It is evident from epidemiological studies that the risk for childhood asthma is increased by having a positive family history of asthma. In particular, allergic sensitization of the newborn is closely linked to maternal but not to paternal allergies. Therefore, we propose that the timing and route of antigen exposure in perinatal life (e.g. transplacental, postnatal oral via breastmilk, or postnatal inhaled) have life-long influences on immune responsiveness that may include heightened sensitivity or tolerance. However, the cells responsible and the mechanisms by which they dictate the functional commitment of the neonate to airway sensitization or tolerance remain to be identified. We will explore how perinatal exposure to the model protein antigen, ovalbumin (OVA), affects development of T- and B cell immune responsiveness. In particular, since it is known that there are ordered waves of T cell development during gestation, with those bearing T cell receptors for antigen (TCR) containing gamma and delta chains (TCRgammadelta cells) appearing first, we will determine how the presence or absence of these cells affects the quantity and quality of the subsequent anti-OVA response. The consequences of perinatal exposure to OVA will be assessed in mice that have reached 6-8 wk of age by comparing the numbers and functional properties of antigen-specific CD4+ TCRalphabeta cells and B cells during immunization (systemic immunity) and aerosol challenge (airway inflammatory response). Thus, we specifically propose to: AIM 1. Determine the impact of perinatal exposure to OVA of parental versus environmental origin on the development of immune responsiveness in offspring. AIM 2. Determine the ability of maternal (or paternal) immune responsiveness to OVA (sensitized vs. tolerant) to modulate immunity to homologous or heterologous antigen in their offspring. AIM 3. Identify populations of leukocytes educated during perinatal life that transfer sensitization or protection to nave mice.