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（由申请人提供）：人类和小鼠的证据表明，免疫调节机制通过母乳从母亲传递给新生儿。然而，某些病原体如呼吸道合胞病毒（RSV）的早期儿童感染会损害这些保护机制，从而在以后的生活中易患疾病（哮喘）。我们的初步数据表明，病毒诱导的Th 2应答在新生小鼠免疫调节机制受损中的作用。在以前的研究中，我们已经显示了调节性T细胞（TcR）表达（mTGF-β）在维持小鼠气道免疫耐受中的重要性。考虑到Tclase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感染是否会损害生命早期的免疫耐受机制。使用我们以前使用的相同的气道耐受模型来证明mTGF-<$在气道耐受中的重要性，最近表明对抗原（Ag）卵清蛋白（OVA）耐受的母亲可以通过母乳将OVA和TGF-<$转移给新生儿。在这项研究中，诱导TdR（iTdR）在母体转移的耐受性中的作用。如果新生儿中的RSV感染可促进过敏性疾病，我们询问Treg介导的免疫抑制是否受到新生儿中病毒感染的损害。事实上，我们的初步数据提供了RSV介导的母体转移耐受性破坏的证据。由于RSV感染促进Th 2应答，因此我们推断，由于在炎症情况下Tcl 3的不稳定性，Tcl 3可能改变表型和功能。我们的初步数据显示，在RSV感染的肺中存在共表达Foxp 3和加塔-3的TcR，其在IL-4 R缺陷小鼠中减弱。我们还显示了从RSV感染的肺中分离的TdR的抑制功能受损。此外，我们已经观察到，与来自未感染的肺的树突状细胞相比，从感染小鼠的肺中分离的树突状细胞具有更活化的表型，并且当暴露于RSV时，诱导TcB的效率较低。这些观察使我们形成了这一提议的主要假设，即RSV感染损害新生儿的母体获得性耐受机制。为了解决这个假设，我们将：目标1。研究病毒诱导的Th 2细胞因子在新生小鼠耐受性和Treg功能受损中的作用。目标2.研究病毒糖蛋白G参与的CX 3CR 1途径在RSV感染新生儿Treg功能受损中的作用。目标3。检查雾化脂质体包封的ATRA恢复小鼠和非人灵长类动物病毒感染肺中Treg功能和气道耐受性的能力。