Pathogenesis of Restrictive Allograft Syndrome Post-Lung Transplantation

肺移植后限制性同种异体移植综合征的发病机制

• 批准号: 10383970
• 负责人: Vibha N Lama
• 金额: $ 70.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383970
• 关键词: 3-Dimensional; Allografting; Antibodies; B-Cell Activation; Bone Marrow; Bortezomib; Cell Maintenance; Cells; Chronic; Communication; Data; Development; Drug Targeting; Exudate; Failure; Fibrosis; Functional disorder; Histologic; Homing; Human; Human Pathology; IL6ST gene; Immune; Immune response; Immunoglobulin G; Immunoglobulin-Secreting Cells; In Situ; In Vitro; Infiltration; Inflammatory; Injury; Interleukin-12; Interleukin-6; Interleukins; Investigation; JAK2 gene; Life; Ligands; Longitudinal Studies; LoxP-flanked allele; Lung; Lung Transplantation; Lymphoid Tissue; Maintenance; Mature B-Lymphocyte; Mesenchymal; Modality; Modeling; Mononuclear; Mus; Outcome; Paracrine Communication; Pathogenesis; Pathology; Perivascular Fibrosis; Pharmacology; Phenotype; Plasma Cells; Plasmablast; Pleura; Pleural; Population; Procedures; Prognosis; Proteasome Inhibitor; Proteins; Publishing; Regulation; Role; STAT3 gene; Savings; Secondary to; Signal Pathway; Signal Transduction; Source; Stromal Cells; Syndrome; Testing; Therapeutic; Time; Transgenic Mice; Transplant Recipients; Transplantation; Tumor-infiltrating immune cells; Up-Regulation; Work; antagonist; anti-CD20; antibody-mediated rejection; chemokine; cost; cytokine; donor-specific antibody; experimental study; hematopoietic tissue; immune activation; in vivo; innovation; insight; lung allograft; lung development; mesenchymal stromal cell; monocyte; mouse model; novel; paracrine; plasma cell differentiation; pre-clinical; preclinical study; prevent; recruit; response; rituximab; single-cell RNA sequencing; spatiotemporal; targeted treatment; therapeutic target; transplant model

PROJECT SUMMARY/ABSTRACT Restrictive allograft syndrome (RAS) is a particularly aggressive form of chronic rejection post-lung transplantation, marked by an extremely poor prognosis (median survival of < 1 year) and little therapeutic options. Pathogenesis of RAS remains elusive although association with donor specific antibodies and antibody mediated rejection have been found in human studies. We have recently characterized a murine lung transplant model which recapitulates the histologic changes of RAS and establishes the requisite role of humoral immune response in its development. A unique feature noted in the murine RAS lung allograft was the presence of activated B cells, plasmablasts, and fully differentiated plasma cell (PCs). PCs were also identified in human RAS lungs suggesting that a rejecting lung serves as an inflammatory local niche for humoral immune responses. These antibody secreting cells (ASCs) localized along the bronchovascular bundles (BVBs) and sub-pleural space, lying in close association with expanding mesenchymal cells (MCs). The key role of specialized stromal cells, via paracrine factors of C-X-C Motif Chemokine Ligand 12 (CXCL12) and interleukin (IL)-6, in establishment of a stable survival niche for ASCs is well recognized across a variety of lymphoid and hematopoietic tissues. We have recently characterized the in situ niche of a subpopulation of lung-resident mesenchymal cells which expand and contribute to fibroproliferation in a RAS allograft. This Foxf1+/Gli1+/Scal1+/Col1+ mesenchymal stromal cell (MSC) population forms a three dimensional network along the bronchovascular bundle (BVB-MSCs). Our new preliminary data demonstrates that these cells are the high CXCL12/IL-6 expressing population, and lie in close apposition to ASCs in the rejecting lung allograft. A novel mechanism of upregulation of CXCL12 expression in BVB-MSCs by IL-6 transsignaling and downstream JAK/Stat activation, with recruited monocytes contributing to the soluble IL-6R, was identified. In this proposal we will investigate an innovative and novel hypothesis of paracrine signaling between this graft-resident mesenchymal stromal cell population and immune cells and the role of IL-6 transsignaling/CXCL12 axis in regulating the humoral inflammatory niche in a rejecting lung. The proposed experiments will utilize our ability to identify and conditionally target the specific BVB-MSC subpopulation, and the novel orthotropic whole lung transplant model of RAS to elucidate the spatial in vivo niche of APCs, its temporal regulation by CXCl12 expressing BVB-MSCs, and its functional significance in the pathogenesis of RAS (Aim 1). The role of IL-6 and IL-6 trans-signaling in cellular communication between resident MCs and infiltrating immune cells within this niche and the pathogenesis of RAS will be determined (Aim 2). The effect of specific drugs targeting humoral cell responses and IL-6 signaling pathway will be tested in the murine lung allograft model of RAS (Aim 3). Together these studies will offer novel mechanistic insight into lung allograft failure and provide pre-clinical information regarding role of therapeutic modalities targeting humoral immune responses in RAS.

项目总结/摘要 限制性同种异体移植物综合征（RAS）是肺移植后慢性排斥反应的一种特别严重的形式， 移植，以极差的预后（中位生存期< 1年）和很少的治疗为标志， 选项. RAS的发病机制尚不清楚，尽管与供体特异性抗体和抗体 在人类研究中发现了介导的排斥。我们最近发现了一种小鼠肺移植 该模型再现了RAS的组织学变化，并建立了体液免疫的必要作用， 在其发展过程中。在鼠RAS肺同种异体移植物中观察到的一个独特特征是 活化的B细胞、浆母细胞和完全分化的浆细胞（PC）。在人类中也发现了PC RAS肺表明排斥肺作为体液免疫应答的炎症局部小生境。 这些抗体分泌细胞（ASCs）分布于沿着支气管血管束（BVB）和胸膜下 间隙，与扩张的间充质细胞（MC）密切相关。特化基质的关键作用 细胞，通过C-X-C基序趋化因子配体12（CXCL 12）和白细胞介素（IL）-6的旁分泌因子， ASC稳定生存生态位的建立在各种淋巴和 造血组织我们最近的特点是在原位生态位的一个亚群的肺居民 在RAS同种异体移植物中，间充质细胞扩增并促进纤维增殖。这 Foxf 1 +/Gli 1 +/Scal 1 +/Col 1+间充质基质细胞（MSC）群体形成三维网络 沿着支气管血管束（BVB-MSCs）。我们新的初步数据表明，这些细胞是 高表达CXCL 12/IL-6的群体，并且在排斥性肺同种异体移植物中与ASC紧密并置。一 IL-6信号转导和下游调控BVB-MSCs中CXCL 12表达的新机制 鉴定了JAK/Stat活化，其中募集的单核细胞有助于可溶性IL-6 R。本提案中 我们将研究一个创新的和新的假说，旁分泌信号之间的这种移植物居民， 间充质基质细胞群和免疫细胞以及IL-6信号转导/CXCL 12轴在 调节排异肺中的体液炎症生态位。拟议中的实验将利用我们的能力， 鉴定并有条件地靶向特定的BVB-MSC亚群，以及新的正交各向异性全肺 RAS的移植模型，以阐明APC的空间体内生态位，其通过CXCl 12的时间调节 表达BVB-MSCs，及其在RAS发病机制中的功能意义（目的1）。IL-6的作用， IL-6在此细胞内驻留MC和浸润免疫细胞之间的细胞通讯中的反式信号传导 生态位和RAS的发病机制将被确定（目的2）。特异性体液靶向药物的作用 将在RAS的鼠肺同种异体移植物模型中测试细胞应答和IL-6信号传导途径（目的3）。 这些研究将为肺移植失败提供新的机制见解，并提供临床前研究。 关于RAS中靶向体液免疫应答的治疗方式的作用的信息。