Lymphatics and Lung Allograft Rejection

淋巴管和肺同种异体移植排斥

• 批准号: 9919614
• 负责人: Souheil El-Chemaly
• 金额: $ 43.12万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919614
• 关键词: Acute; Address; Allogenic; Allografting; Antigen Presentation; Beds; Biopsy; Blocking Antibodies; Bronchoalveolar Lavage Fluid; CD44 Antigens; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Complication; Data; Development; Endothelium; Extracellular Matrix; Fluorescence; Genes; Graft Rejection; Human; Hyaluronan; Image; Immunosuppression; Implant; Inflammatory; Isogenic transplantation; Lead; Lung; Lung Transplantation; Lung diseases; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Mediating; Modification; Molecular; Molecular Weight; Monitor; Mus; Natural regeneration; Outcome; Patients; Play; Principal Investigator; Proteins; Publishing; Quality of life; Research; Resolution; Respiratory physiology; Risk Factors; Rodent; Role; Serum; Solid; Structure of parenchyma of lung; Surface; Time; Tissues; Transgenic Animals; Transplant Recipients; Transplantation; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; allograft rejection; base; clinical efficacy; cohort; density; draining lymph node; early detection biomarkers; experimental study; graft function; idiopathic pulmonary fibrosis; implantation; improved; in vivo; inhibitor/antagonist; injury and repair; insight; lung allograft; lung injury; lymphatic circulation; lymphatic vasculature; lymphatic vessel; novel; novel strategies; novel therapeutics; organ transplant rejection; peripheral blood; post-transplant; programs; receptor; receptor function; response; therapeutic target; transplant model; treatment response

Program Director/Principal Investigator (Last, First, Middle): El-Chemaly, Souheil, Y Abstract Lung transplantation remains the only therapy proven to prolong survival and improve quality of life in advanced lung diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. The median survival after transplantation is currently 5.3 years. Little is known about the importance and function of the lymphatic circulation after graft has been implanted and subjects develop acute and/or chronic rejection. A key question is whether post-transplantation lymphangiogenesis is detrimental (e.g. by promoting antigen presentation within draining lymph nodes and stimulating alloimmune responses) or beneficial (e.g. by promoting efficient inflammatory cell clearance). One key molecule is Hyaluronan (HA) which plays critical roles in lung injury and repair and importantly, HA plays a role in transplant rejection. The turnover of HA (several grams/day in humans) occurs primarily in the lymphatics that catabolize approximately 85% of HA. Lymphatic vessel endothelial HA receptor (LYVE-1) is an endocytic receptor for HA on the surface of lymphatic endothelial cells (LEC). In compelling published and preliminary data, we show that in mice recipient of an allogeneic lung graft there is a decrease in lymphatic vessels density in acute rejection. Importantly, stimulating lymphangiogenesis after rejection has been established resulted in improved rejection and lung allograft function. Importantly, the beneficial effects of induction of lymphangiogenesis were abrogated by co-treatment with LYVE-1 function blocking antibodies, suggesting important role(s) for LYVE-1 in inflammatory lung conditions. Based on these findings we propose as a guiding hypothesis that re-establishing the integrity of the lymphatic vasculature through donor lymphatic endothelial cells is critical for HA clearance and the resolution of acute lung rejection. Key corollaries are that targeting the lymphatic vasculature will have clinical efficacy in lung transplant; and that lymphatic-dependent molecules are detectable in the lung microenvironment and in sera of patients with acute lung rejection. To address our hypotheses, we propose these Specific Aims: Aim 1: To identify the origin of lymphatic endothelial cells in lymphatic vessel regeneration after lung transplantation. To determine mechanisms whereby lymphangiogenesis protects against lung allograft rejection. Aim 3: To demonstrate that lymphatic specific changes in lung tissue and peripheral blood can predict acute lung rejection and response to therapy. If successful, this research will provide new insights into the mechanisms underlying the influence of lymhangiogenesis on lung tissue and the role the lymphatic circulation plays in vivo in lung rejection. In addition, it will pave the way for the development of novel strategies to treat acute rejection in lung transplant recipients. PHS 398/2590 (Rev. 06/09) Research strategy Page

项目负责人/主要研究者（最后一名、第一名、中间名）：El-Chemaly，Souheil，Y 摘要 肺移植仍然是唯一被证明可以延长晚期肺部疾病（如慢性阻塞性肺病和特发性肺纤维化）的生存期和改善生活质量的治疗方法。目前移植后的中位生存期为5.3年。很少有人知道的重要性和功能的淋巴循环后，移植物已被植入和受试者发生急性和/或慢性排斥反应。一个关键问题是移植后淋巴管生成是有害的（例如通过促进引流淋巴结内的抗原呈递和刺激同种免疫应答）还是有益的（例如通过促进有效的炎性细胞清除）。其中一个关键分子是透明质酸（HA），它在肺损伤和修复中起关键作用，重要的是，HA在移植排斥反应中起作用。HA的周转（人体中为几克/天）主要发生在分解代谢约85% HA的代谢物中。淋巴管内皮HA受体（LYVE-1）是淋巴管内皮细胞（LEC）表面HA的内吞受体。在令人信服的已发表和初步的数据，我们表明，在小鼠受体的同种异体肺移植有一个淋巴管密度下降，在急性排斥反应。重要的是，在排斥反应发生后刺激淋巴管生成可改善排斥反应和肺移植功能。重要的是，诱导淋巴管生成的有益作用通过与LYVE-1功能阻断抗体的共治疗而消除，表明LYVE-1在炎性肺病症中的重要作用。基于这些发现，我们提出了一个指导性假设，即通过供体淋巴管内皮细胞重建淋巴管系统的完整性对于HA清除和急性肺排斥反应的解决至关重要。关键的推论是靶向淋巴管系统将在肺移植中具有临床疗效;并且在肺微环境和急性肺排斥患者的血清中可检测到血管依赖性分子。为了解决我们的假设，我们提出了这些具体的目的：目的1：确定淋巴管内皮细胞在肺移植后淋巴管再生的起源。探讨淋巴管生成对肺移植排斥反应的保护机制。目的3：证实肺组织和外周血淋巴细胞特异性改变可预测急性肺 排斥和对治疗的反应。如果成功，这项研究将提供新的见解的机制的影响，肺组织和淋巴循环在体内肺排斥反应中发挥的作用，hangiogenesis。此外，它将为开发治疗肺移植受者急性排斥反应的新策略铺平道路。 PHS 398/2590（Rev.06/09） 研究战略Page

项目成果

Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation.

• DOI: 10.1371/journal.pone.0194193
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: El-Chemaly S;O'Brien KJ;Nathan SD;Weinhouse GL;Goldberg HJ;Connors JM;Cui Y;Astor TL;Camp PC Jr;Rosas IO;Lemma M;Speransky V;Merideth MA;Gahl WA;Gochuico BR
• 通讯作者: Gochuico BR

The Immunome in Two Inherited Forms of Pulmonary Fibrosis.

• DOI: 10.3389/fimmu.2018.00076
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: El-Chemaly S;Cheung F;Kotliarov Y;O'Brien KJ;Gahl WA;Chen J;Perl SY;Biancotto A;Gochuico BR
• 通讯作者: Gochuico BR

Alemtuzumab as a Therapy for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients With Short Telomeres.

阿仑单抗用于治疗端粒短的肺移植受者的慢性肺同种异体移植功能障碍。

• DOI: 10.3389/fimmu.2020.01063
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Trindade,AnilJ;Thaniyavarn,Tany;Townsend,Keri;Klasek,Robin;Tsveybel,KarenP;Kennedy,JohnC;Goldberg,HilaryJ;El-Chemaly,Souheil
• 通讯作者: El-Chemaly,Souheil