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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要限制性同种异体移植综合征（RAS）是一种特别具有侵略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<1年）且治疗效果甚微选项。尽管与供体特异性抗体和抗体相关，但 RAS 的发病机制仍然难以捉摸在人类研究中发现了介导的排斥反应。我们最近对小鼠肺移植进行了表征该模型概括了 RAS 的组织学变化并确立了体液免疫的必要作用其发展中的反应。小鼠 RAS 肺同种异体移植物中的一个独特特征是存在活化的 B 细胞、浆母细胞和完全分化的浆细胞 (PC)。人类中也发现了 PC RAS 肺表明排斥性肺是体液免疫反应的炎症局部生态位。这些抗体分泌细胞 (ASC) 位于支气管血管束 (BVB) 和胸膜下空间，与扩张的间充质细胞（MC）密切相关。特殊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 (IL)-6 的旁分泌因子，建立 ASC 稳定的生存环境已被多种淋巴和组织广泛认可造血组织。我们最近描述了肺居民亚群的原位生态位间充质细胞在 RAS 同种异体移植物中扩张并促进纤维增殖。这 Foxf1+/Gli1+/Scal1+/Col1+间充质基质细胞（MSC）群形成三维网络沿着支气管血管束（BVB-MSC）。我们新的初步数据表明这些细胞是 CXCL12/IL-6 高表达群体，并且与排斥性肺同种异体移植物中的 ASC 紧密相连。一个通过IL-6转信号和下游上调BVB-MSC中CXCL12表达的新机制鉴定出 JAK/Stat 激活，其中募集的单核细胞有助于可溶性 IL-6R。在这个提案中我们将研究这种移植物驻留者之间的旁分泌信号传导的创新假设间充质基质细胞群和免疫细胞以及 IL-6 转信号/CXCL12 轴在调节排斥性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并有条件地靶向特定的 BVB-MSC 亚群，以及新型正交各向异性全肺 RAS移植模型阐明APC的体内空间生态位及其受CXCl12的时间调节表达 BVB-MSC 及其在 RAS 发病机制中的功能意义（目标 1）。 IL-6的作用和常驻 MC 与浸润免疫细胞之间的细胞通讯中的 IL-6 反式信号传导将确定 RAS 的生态位和发病机制（目标 2）。特定药物针对体液的作用将在 RAS 小鼠同种异体肺移植模型中测试细胞反应和 IL-6 信号通路（目标 3）。这些研究共同将为肺同种异体移植失败提供新的机制见解，并提供临床前研究关于针对 RAS 体液免疫反应的治疗方式的作用的信息。