HSCT-induced alterations in DCs to promote IL-17 and lung pathology

HSCT 诱导的 DC 改变促进 IL-17 和肺部病理学改变

• 批准号: 9276115
• 负责人: Bethany B. Moore
• 金额: $ 48.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276115
• 关键词: Acute; Address; Adoptive Transfer; Allogenic; Autologous; Autophagocytosis; Bone Marrow Transplantation; Bronchiolitis Obliterans; Cell physiology; Cells; Chronic; Complication; Data; Dendritic Cells; Development; Diagnosis; Disease; Fibrosis; Functional disorder; Genetic; Goals; Hematopoietic Stem Cell Transplantation; Hereditary Disease; Herpesviridae; Herpesviridae Infections; Homeostasis; Human; Idiopathic pneumonia syndrome; Immune response; Impairment; Incidence; Infection; Inflammasome; Inflammation; Inherited; Interleukin-1 beta; Interleukin-17; Interleukin-6; Interstitial Pneumonia; Lead; Ligands; Lung; Lytic; Lytic Phase; Malignant - descriptor; Malignant Neoplasms; Molecular; Morbidity - disease rate; Mus; Pathologic; Pathology; Patients; Phenotype; Play; Pneumonia; Population; Procedures; Process; Publishing; Pulmonary Inflammation; Pulmonary Pathology; Reporting; Research; Respiratory physiology; Role; Safety; Signal Transduction; Stem cell transplant; T cell response; T-Lymphocyte; Testing; Th1 Cells; Time; Tissues; Transforming Growth Factor beta; Transplantation; Vasculitis; Virus; Virus Diseases; Work; experience; gammaherpesvirus; immunopathology; interleukin-23; lung development; mortality; mouse model; notch protein; novel; receptor; reconstitution; respiratory virus; response; success; trafficking

Abstract: Hematopoietic stem cell transplantation (HSCT) is a curative option for the treatment of numerous malignancies and inherited genetic disorders; however, the success of the procedure is hampered by numerous complications. Pulmonary complications cause significant morbidity and mortality following HSCT and most notably include infections, idiopathic pneumonia syndrome (IPS), bronchiolitis obliterans (BOS) and cryptogenic organizing pneumonia (COP). These conditions are characterized by acute and chronic inflammation and can include tissue fibrosis, severely damaging lung function. While more common following allogeneic HSCT, IPS, BOS and COP have also been reported as a complication of autologous HSCT and their diagnosis is defined, in part, by the absence of infection. However, accumulating evidence suggests these lung pathologies could represent immunopathology that develops as a consequence of a previous viral infection, or possibly due to an occult infection. Importantly, herpesviruses were recently identified as the most common occult infection in patients with IPS. We have developed a murine model in which syngeneic bone marrow transplant (BMT) mice that are fully reconstituted with donor-derived cells develop severe lung pathology characterized by interstitial pneumonitis, vasculitis and fibrosis following infection with murine gamma herpesvirus-68 (γHV-68). This lung pathology is well established at 21 days post-infection when lytic viral infection has been cleared and the virus has established latency. Our published and preliminary findings suggest the process of BMT alters the phenotype of lung dendritic cells (DCs). DCs from BMT mice overproduce IL-1β, IL-6, TGFβ and IL-23. These BMT-induced DC alterations lead to the skewing of the CD4 response to a Th17, rather than a Th1 response post-infection with γHV-68. The consequence of this persistent skewing is the development of IL-17-dependent pneumonitis and fibrosis. In addition, we have evidence that adoptive transfer of DCs from infected control mice into BMT mice can restore Th1 cell priming and limit development of lung immunopathology focusing our current studies on trying to understand how the process of BMT impairs the function of lung DCs. Preliminary data suggest that lung DCs in BMT mice are characterized by reduced autophagy and impaired expression of the Notch ligand, delta like ligand 4 (DLL4). Reduced autophagy could explain the overproduction of IL-1β if DCs in BMT mice are unable to clear activated inflammasomes. Notch signaling is highly context-dependent and can both enhance and inhibit T cell signaling. Thus, the overall goal of the proposed research is to mechanistically understand how DCs are altered following HSCT in ways that promote pathologic rather than protective immune responses to respiratory viruses. Most importantly, we will determine whether these molecular alterations that characterize murine DCs post-BMT are also evident in DCs from human patients experiencing lung dysfunction post-HSCT. Our hypothesis is that HSCT results in reduced autophagy and impaired DLL4 expression in lung DCs in response to γHV-68 infection, and that this alteration in DCs promotes pathologic Th17 rather than protective Th1 responses. We will address this hypothesis in the following specific aims. Aim 1) To identify the relevant DC population responsible for priming γHV-68-specific T cell responses and determine whether autophagy is impaired in these DCs post-BMT and γHV-68 infection Aim 2) To determine if BMT DCs are characterized by defective Notch ligand expression or altered costimulatory receptors Aim 3) To determine the translational relevance of these findings by determining whether the responses are specific to γ-herpesviruses, and whether similar DC phenotypes are noted in patients post-HSCT Completion of these specific aims will be significant for several reasons. This work will solidify the critical role that latent or occult infection play in causing “idiopathic” lung pathology post-HSCT and will provide novel information regarding the mechanistic alterations that occur in DCs post-transplant. Most importantly, this work will identify and test strategies to restore DC function post-BMT and will provide translational proof that these phenotypes characterize human DCs post-HSCT.

翻译后摘要：造血干细胞移植（HSCT）是一种治疗的选择，为治疗许多 恶性肿瘤和遗传性遗传疾病;然而，手术的成功受到以下因素的阻碍： 许多并发症。肺部并发症导致HSCT后显著的发病率和死亡率 最值得注意的包括感染、特发性肺炎综合征（IPS）、闭塞性细支气管炎（BOS）和 隐源性机化性肺炎（COP）。这些疾病的特点是急性和慢性 炎症，并可包括组织纤维化，严重损害肺功能。虽然更常见的是 同种异体HSCT、IPS、BOS和COP也被报道为自体HSCT的并发症， 他们的诊断部分是通过没有感染来确定的。然而，越来越多的证据表明， 这些肺部病理学可能代表了由于之前的病毒而发展的免疫病理学 感染，或可能是由于隐性感染。重要的是，疱疹病毒最近被确定为最常见的病毒。 IPS患者常见的隐匿性感染。我们建立了一个小鼠模型， 用供体来源的细胞完全重建的骨髓移植（BMT）小鼠发生严重的肺 病理学特征为间质性肺炎，血管炎和纤维化后感染鼠 γ疱疹病毒-68（γHV-68）。这种肺部病理学在感染后21天得到了很好的建立， 病毒感染已被清除，病毒已建立潜伏期。我们发表的和初步的研究结果 提示BMT过程改变了肺树突状细胞（DC）的表型。来自BMT小鼠的DC 过量产生IL-1β、IL-6、TGFβ和IL-23。这些BMT诱导的DC改变导致CD 4+细胞的偏斜。 Th 17应答，而不是γHV-68感染后的Th 1应答。这样做的后果 持续的偏斜是IL-17依赖性肺炎和纤维化的发展。另外我们有 从感染对照小鼠中过继转移DC到BMT小鼠中可以恢复Th 1细胞启动的证据 并限制了肺免疫病理学的发展，我们目前的研究集中在试图了解 BMT过程损害肺DCs的功能。初步数据表明，BMT小鼠的肺DCs 其特征在于减少的自噬和Notch配体δ样配体4（DLL 4）的表达受损。 如果BMT小鼠中的DC不能清除活化的IL-1β，则自噬减少可以解释IL-1β的过度产生。 炎性小体Notch信号具有高度的环境依赖性，可以增强和抑制T细胞增殖， 发信号。因此，拟议研究的总体目标是从机制上了解DC是如何 在HSCT后以促进病理性而非保护性免疫反应的方式改变， 呼吸道病毒最重要的是，我们将确定这些分子改变是否表征了 BMT后的鼠DC在来自HSCT后经历肺功能障碍的人患者的DC中也是明显的。 我们的假设是，HSCT导致肺DCs自噬减少和DLL 4表达受损。 DCs中的这种改变促进了病理性Th 17，而不是Th 17的表达。 保护性Th 1应答。我们将在以下具体目标中讨论这一假设。 目的1）鉴定负责引发γHV-68特异性T细胞应答的相关DC群体， 确定BMT和γHV-68感染后这些DC中的自噬是否受损 目的2）确定BMT DC的特征是否在于缺陷的Notch配体表达或改变的Notch配体表达。 共刺激受体 目的3）通过确定这些反应是否符合 特异于γ-疱疹病毒，以及HSCT后患者中是否观察到相似的DC表型 这些具体目标的完成具有重要意义，原因有几个。这项工作将巩固关键作用 潜在或隐匿性感染在HSCT后引起“特发性”肺病理中起作用， 关于移植后DC中发生的机械改变的信息。最重要的是，这项工作 将确定和测试策略，以恢复DC功能后BMT，并将提供翻译证明，这些 表型表征HSCT后的人DC。