Understanding Protective Immunoregulatory Mechanisms in the Infant Lung

描述(申请人提供)：在人类和小鼠身上的证据表明，免疫调节机制是通过母乳从母亲传播给新生儿的。然而，儿童早期感染某些病原体，如呼吸道合胞病毒(RSV)，破坏了这些保护机制，从而容易在以后的生活中患上疾病(哮喘)。我们的初步数据表明，病毒诱导的Th2反应在新生小鼠免疫调节机制受损中发挥了作用。在以前的研究中，我们已经证明了调节性T细胞(Treg)表达(mTGF-β)在维持小鼠呼吸道免疫耐受中的重要性。鉴于Tregs在抑制呼吸道无根据的过敏反应中的重要作用，我们调查了RSV感染是否损害了早期生命的免疫耐受机制。使用我们以前使用的相同的呼吸道耐受模型来证明mTGF-β在呼吸道耐受中的重要性，最近的研究表明，对抗原(Ag)卵清蛋白(OVA)耐受的母亲可以通过母乳将OVA和TGF-β转移给她们的新生儿。本研究提出了诱导Tregs(ITregs)在母体转移耐受中的作用。如果新生儿中的RSV感染会促进变态反应性疾病，我们询问新生儿中的病毒感染是否会损害Treg介导的免疫抑制。事实上，我们的初步数据提供了RSV介导的母体转移耐受性被打破的证据。由于RSV感染促进了Th2应答，我们推测Tregs可能会由于Tregs在炎症环境中的不稳定性而改变表型和功能。我们的初步数据显示，在RSV感染的肺中存在共表达Foxp3和GATA-3的Tregs，在IL-4R缺陷小鼠中这种表达减弱。我们还发现从RSV感染的肺中分离的Tregs的抑制功能受损。此外，我们还观察到，从感染小鼠的肺部分离的树突状细胞比从未感染的肺分离的树突状细胞具有更活跃的表型，并且当暴露于RSV时，诱导Treg的效率较低。这些观察结果使我们形成了这一建议的主要假设，即RSV感染损害了新生儿的母体获得性耐受机制。为了解决这一假设，我们将：目的1.研究病毒诱导的Th2细胞因子在新生小鼠耐受性和Treg功能损害中的作用。目的2.研究病毒糖蛋白G参与的CX3CR1途径在呼吸道合胞病毒感染新生儿Treg功能损害中的作用。目的3.检测全反式维甲酸雾化脂质体对病毒感染小鼠和非人灵长类动物肺Treg功能和气道耐受性的恢复能力。

DESCRIPTION (provided by applicant): Evidence in both humans and mice shows that immunoregulatory mechanisms are transmitted from mothers to their newborns via breast milk. However, early childhood infections by certain pathogens such as respiratory syncytial virus (RSV) compromise these protective mechanisms thereby predisposing to disease (asthma) later in life. Our preliminary data suggest a role for virus-induced Th2 responses in impairment of immunoregulatory mechanisms in newborn mice. In previous studies we have shown the importance of regulatory T cells (Tregs) expressing (mTGF-¿) in maintaining immune tolerance in the airways of mice. Given the important role of Tregs in suppressing unwarranted allergic responses in the airways, we investigated whether RSV infection compromises immune tolerance mechanisms in early life. Using the same model of airway tolerance previously used by us to demonstrate the importance of mTGF-¿ in airway tolerance, it was recently shown that mothers tolerized to the antigen (Ag) ovalbumin (OVA) can transfer OVA and TGF-¿ to their newborns via breast milk. A role for induced Tregs (iTregs) in maternally-transferred tolerance was presented in this study. If RSV infection in newborns can promote allergic disease, we asked whether Treg-mediated immune suppression is compromised by viral infection in the newborns. Indeed, our preliminary data provide evidence of RSV-mediated breach of maternally-transferred tolerance. Since RSV infection promotes Th2 responses, we reasoned that Tregs might change phenotype and function due to instability of Tregs in the context of inflammation. Our preliminary data show the presence of Tregs co- expressing Foxp3 and GATA-3 in RSV infected lungs, which is attenuated in IL-4R-deficient mice. We also show impairment of suppressive function of Tregs isolated from RSV-infected lungs. Additionally, we have observed that dendritic cells isolated from the lungs of infected mice have a more activated phenotype compared to those from uninfected lungs and when exposed to RSV are less efficient in inducing Tregs. These observations lead us to formulate the major hypothesis of this proposal, which is that RSV infection impairs maternally-acquired tolerance mechanisms in newborns. To address this hypothesis we will: Aim 1. Investigate the role of virus-induced Th2 cytokines in impairment of tolerance and Treg function in newborn mice. Aim 2. Study the contribution of the CX3CR1 pathway engaged by the viral glycoprotein G in impairment of Treg function in RSV-infected neonates. Aim 3. Examine the ability of aerosolized liposome-encapsulated ATRA to restore Treg function and airway tolerance in virus-infected lungs of mice and non-human primates.