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气道炎症发展的影响。流行病学研究表明，有哮喘家族史的儿童患哮喘的风险明显增加。特别是，新生儿的过敏反应与母亲密切相关，而与父亲过敏无关。因此，我们认为围产期抗原暴露的时间和途径（如经胎盘、产后经母乳口服或产后吸入）对免疫反应性有终身影响，可能包括敏感性或耐受性的提高。然而，负责的细胞和它们决定新生儿气道致敏或耐受的功能承诺的机制仍有待确定。我们将探讨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，首先出现的是那些携带含有γ链和δ链的T细胞抗原受体（TCR）的细胞（tcrgamma - δ细胞），我们将确定这些细胞的存在或不存在如何影响随后抗ova反应的数量和质量。通过比较免疫（全身免疫）和气溶胶攻击（气道炎症反应）期间抗原特异性CD4+ tcrα细胞和B细胞的数量和功能特性，将评估6-8周龄小鼠围产期暴露于OVA的后果。因此，我们特别建议：AIM 1。确定围产期暴露于亲本和环境来源的卵细胞对后代免疫反应性发育的影响。目标2。测定母本（或父本）对卵磷脂的免疫反应（致敏性与耐受性）调节后代对同源或异源抗原的免疫能力。目标3。鉴定围产期受教育的白细胞群，这些白细胞将致敏或保护作用传递给幼鼠。

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.