Understanding Protective Immunoregulatory Mechanisms in the Infant Lung

了解婴儿肺的保护性免疫调节机制

• 批准号: 8711267
• 负责人: Prabir Ray
• 金额: $ 43.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711267
• 关键词: Address; Adult; Allergic Disease; Antibodies; Antigens; Asthma; Attenuated; Binding; Biological Assay; Birth; CD4 Positive T Lymphocytes; CX3CL1 gene; Cell physiology; Cells; Characteristics; Data; Dendritic Cells; Disease; Effector Cell; Encapsulated; GTP-Binding Proteins; Goals; Human; Human Milk; Hyperplasia; Immune Tolerance; Immunosuppression; Impairment; Infant; Infection; Inflammation; Interleukin-13; Interleukin-4; Lead; Life; Liposomes; Literature; Lung; Lung diseases; Mediating; Modeling; Monoclonal Antibodies; Mothers; Mucous body substance; Mus; Neonatal; Newborn Infant; Ovalbumin; Pathway interactions; Phenotype; Play; Production; Pulmonary Pathology; Recurrence; Regulatory T-Lymphocyte; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV G glycoprotein; Risk; Role; Signal Transduction; Sorting - Cell Movement; Stress; Tretinoin; Viral; Virus; Virus Diseases; aerosolized; allergic response; attenuation; cytokine; early childhood; fetal; glycoprotein G; human CX3CR1 protein; in vivo; mouse model; neonate; nonhuman primate; novel; pathogen; research study; respiratory; response; transcription factor

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.

描述（由适用提供）：人类和小鼠的证据都表明，免疫调节机制是通过母乳从母亲传播到新生儿的。然而，某些病原体（例如呼吸道合胞病毒（RSV））的幼儿感染损害了这些受保护的机制，从而使疾病（哮喘）的生命更晚。我们的初步数据表明，病毒诱导的Th2反应在新生小鼠的免疫调节机制中起作用。在先前的研究中，我们已经表明了调节T细胞（Tregs）表达（MTGF- - ）在维持小鼠气道中免疫耐受性方面的重要性。鉴于Treg在抑制气道中不必要的过敏反应中的重要作用，我们研究了RSV感染是否会损害早期生命中的免疫耐受性机制。使用美国以前使用的相同的气道耐受性模型来证明MTGF- - 在气道耐受性中的重要性，最近表明，耐受对抗原（Ag）卵巢蛋白（OVA）的母亲可以通过母乳将OVA和TGF- - 可以通过母乳将OVA和TGF-¿转移到新生儿。本研究提出了诱导的Treg（ITREGS）在母体转移的公差中的作用。如果新生儿中的RSV感染可以促进过敏性疾病，我们询问新生儿中病毒感染是否会损害Treg介导的免疫抑制。实际上，我们的初步数据提供了RSV介导的违反母体转移耐受性的证据。由于RSV感染促进了Th2反应，因此我们认为Tregs可能会因感染中Treg的不稳定性而改变表型和功能。我们的初步数据表明，在RSV感染的肺中，Tregs共表达FOXP3和GATA-3，该肺在IL-4R缺乏小鼠中减弱。我们还显示了从RSV感染的肺中分离出的Treg的抑制功能的损害。此外，我们已经观察到，与未感染的肺部相比，从感染小鼠的肺中分离出的树突状细胞具有更激活的表型，而在暴露于RSV时，在诱导的Treg中效率较低。这些观察结果使我们提出了该提案的主要假设，即RSV感染损害了新生儿中主要获得的耐受性机制。为了解决这一假设，我们将：目标1。研究病毒诱导的Th2细胞因子在新生小鼠中耐受性和Treg功能障碍中的作用。 AIM 2。研究病毒糖蛋白G在RSV感染的新生儿中降低Treg功能的CX3CR1途径的贡献。 AIM 3。检查雾化脂质体封装ATRA恢复小鼠病毒感染肺和非人类隐私的Treg功能和气道耐受性的能力。