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: 10532251
• 负责人: Vibha N Lama
• 金额: $ 67.11万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532251
• 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-6; Interleukins; Investigation; JAK2 gene; Life; Ligands; Longitudinal Studies; LoxP-flanked allele; Lung; Lung Transplantation; Lymphoid Tissue; Lymphoplasmacytic Infiltrate; Maintenance; Mature B-Lymphocyte; Mesenchymal; Modality; Modeling; Mononuclear; Mus; Outcome; Paracrine Communication; Pathogenesis; Pathology; Perivascular Fibrosis; Phenotype; Plasma Cells; Plasmablast; Pleura; Population; Procedures; Prognosis; Proteasome Inhibitor; Proteins; Publishing; Regulation; Role; STAT3 gene; Secondary to; Signal Pathway; Signal Transduction; Source; Stromal Cell-Derived Factor 1; Stromal Cells; Syndrome; Testing; Therapeutic; Time; Transgenic Mice; Transplant Recipients; Transplantation; Up-Regulation; Work; antagonist; anti-CD20; antibody-mediated rejection; chemokine; cost; cytokine; donor-specific antibody; experimental study; hematopoietic tissue; humoral immunity deficiency; immune activation; immune cell infiltrate; in vivo; innovation; insight; lung allograft; lung development; mesenchymal stromal cell; monocyte; mouse model; novel; paracrine; pharmacologic; 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.

项目摘要/摘要 限制性同种异体移植综合征(RAS)是一种特别侵袭性的肺后慢性排斥反应。 移植，其特点是预后极差(中位生存期为1年)，且几乎没有治疗作用 选择。RAS的发病机制仍不清楚，尽管与供者特异性抗体和抗体有关 在人体研究中已经发现了介导性排斥反应。我们最近描述了一种小鼠肺移植 一种概括RAS组织学变化并确立体液免疫所必需作用的模型 在其发展中做出回应。在小鼠RAS肺移植中注意到的一个独特的特征是存在 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肺提示排斥肺是体液免疫反应的局部炎症性小生境。 这些抗体分泌细胞(ASCs)沿支气管血管束和胸膜下分布。 间隙，与扩张的间充质细胞(MC)密切相关。专门化基质的关键作用 细胞通过C-X-C基序趋化因子配体12(CXCL12)和白细胞介素6(IL-6)旁分泌因子，在 ASCs的稳定生存生态位的建立在各种淋巴和 造血组织。我们最近描述了肺部居民亚群的原位生态位。 间充质细胞在RAS同种异体移植物中的扩张和促进纤维增殖。这 Foxf1+/Gli1+/Scal1+/Col1+间充质基质细胞群形成三维网络 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 CXCL12/IL-6高表达人群，与排斥肺移植中的ASCs关系密切。一个 IL-6转导及下游上调BVB-MSCs CXCL12表达的新机制 JAK/STAT被激活，募集的单核细胞参与了可溶性IL-6R的产生。在本建议书中 我们将研究一种创新和新颖的假说，即移植物驻留患者之间的旁分泌信号 骨髓间充质细胞群和免疫细胞及IL-6转导/CXCL12轴的作用 调节排斥肺中的体液炎症生态位。拟议的实验将利用我们的能力 识别和有条件地靶向特定的BVB-MSC亚群和新的正交异性全肺 RAS移植模型阐明APC在体内的空间生态位及CXCL12对其时间调控 BVB-MSCs的表达及其在RAS发病机制中的作用(目的1)。IL-6和IL-6的作用 IL-6在常驻MC与免疫细胞间的细胞通讯中的反式信号转导 将确定RAS的生态位和发病机制(目标2)。针对体液的特异性药物的作用 将在RAS(AIM 3)的小鼠肺移植模型中测试细胞反应和IL-6信号通路。 总之，这些研究将为同种异体肺移植失败提供新的机制洞察，并提供临床前 关于针对体液免疫反应的治疗方式在RAS中的作用的信息。