Perinatal Antigen Exposure and Allergic Asthma

本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，有阳性哮喘家族史的儿童哮喘风险增加。 特别是，新生儿的过敏性致敏与母亲的过敏密切相关，但与父亲的过敏无关。因此，我们提出，在围产期的抗原暴露的时间和途径（例如，经胎盘，出生后口服母乳，或出生后吸入）对免疫反应，可能包括提高敏感性或耐受性的终身影响。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。 我们将探讨如何围产期暴露于模型蛋白抗原，卵清蛋白（OVA），影响T和B细胞免疫反应的发展。 特别是，因为它是已知的，有有序波的T细胞发育在妊娠期间，与那些轴承T细胞受体抗原（TCR）含有γ和δ链（TCR γ δ细胞）出现第一，我们将确定这些细胞的存在或不存在如何影响的数量和质量的后续抗OVA反应。 通过比较免疫（全身免疫）和气溶胶激发（气道炎症反应）期间抗原特异性CD 4 + TCR α细胞和B细胞的数量和功能特性，在已达到6-8周龄的小鼠中评估围产期暴露于OVA的后果。 因此，我们具体建议：目标1。确定围产期暴露于父母与环境来源的OVA对后代免疫反应性发展的影响。 AIM 2.确定母体（或父体）对OVA的免疫应答（致敏与耐受）调节其后代对同源或异源抗原的免疫的能力。 AIM 3.识别在围产期接受教育的白细胞群体，这些白细胞将致敏性或保护性转移至NAve mice.

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.