Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation

调节内皮细胞免疫代谢和线粒体形态对器官移植的影响

基本信息

批准号：
10634543
负责人：
SATISH N NADIG
金额：
$ 39.79万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10634543
关键词：
Acute Affect Alloantigen Allograft Tolerance Allografting Antigen Presentation Antigen-Presenting Cells Antiinflammatory Effect Blood Vessels Brain Death Cell Communication Cell Line Cells Cessation of life Chronic Cryopreservation Data Dose Endothelial Cells Endothelium Environment Event Functional disorder Goals Graft Rejection Graft Survival Heart Transplantation Heterogeneity Imaging Techniques Immune Immunity Immunologics Immunosuppression In Vitro Infection Infiltration Inflammatory Injury Ischemia Laboratories Link Longevity Mainstreaming Maintenance Malignant Neoplasms Mediating Metabolic Metabolism Mitochondria Modeling Morphology Mus Organ Organ Preservation Organ Procurements Organ Transplantation Organ failure Pathology Patients Peptides Pharmaceutical Preparations Phase Phenotype Play Process Regimen Reperfusion Injury Reperfusion Therapy Role Severities Shapes Solid Stress T memory cell T-Cell Activation T-Lymphocyte Therapeutic Therapeutic immunosuppression Time Transplantation Tubular formation Vascular Diseases Vertebral column allograft rejection clinical translation clinically relevant curative treatments cytokine effector T cell end-stage organ failure experimental study functional outcomes graft dysfunction graft failure immune function immunogenic immunogenicity immunological synapse implantation improved improved outcome in vivo in vivo Model inhibitor ischemic injury metabolic profile natural hypothermia novel novel strategies novel therapeutic intervention post-transplant preconditioning preservation programs promoter response side effect small molecule standard of care stressor synaptic function transplant model

项目摘要

ABSTRACT: Organ transplantation is a mainstream therapy for patients with organ failure; however, despite major advances in the field, there has been little progress regarding two major components of transplantation -- organ preservation and maintenance immunosuppression. Although essential, immunosuppressive therapy carries a significant side-effect burden, often leading to patient death and graft failure. In addition, the process of organ procurement most often includes use of grafts from brain dead donors followed by hypothermic preservation of the organs in storage solutions. During these events, the endothelial cells (EC) in the organ allografts are primed immunologically and are then subjected to the insults of reperfusion. This early injury predisposes the EC to inappropriate antigen presentation and effects of chronic graft dysfunction, including graft vasculopathy leading to long-term graft failure. Hypothermic preservation changes the metabolism of the allograft, which in turn is hypothesized to alter the immunogenicity of the ECs ultimately affecting cellular functional outcomes. Central to this cascade is the role of the mitochondria in shaping the immunometabolic milieu of the allograft in the face of cold ischemia and reperfusion injury. In this proposal we, for the first time, explore the mechanistic relationship between the mitochondrial morphology and immunometabolism of ECs and their immunogenicity in the setting of transplantation. We build upon our own data to assess the effects of forcing mitochondrial ultrastructural changes on the immunogenic profile of EC during the preservation phase of transplantation. We propose that by dampening the early immunogenic effects of ECs, we can create the opportunity to induce allograft tolerance with the use of reduced immunosuppressive regimens thereby reducing the deleterious consequences of these necessary drugs. We will employ the scientific premise of reprograming ECs to a more tolerogenic state by altering their metabolic core such that their ability to induce proinflammatory changes from alloreactive T cells are diminished. Using clinically relevant in vivo models of transplantation, we anticipate that altering EC mitochondria will improve graft survival and abrogate the pathology associated with allograft rejection. Using our preliminary data as a backbone we hypothesize that cold ischemia exacerbates the immunogenic capacity and metabolic profile of EC by altering mitochondrial morphology resulting in allograft injury. Additionally, with the following aims, our goal will be to protect organ allografts and skew the EC to a more tolerogenic phenotype. Aim 1. We will determine the impact of mitochondrial morphology during organ preservation on the immunogenicity of endothelial cells in vitro. Aim 2. We aim to assess the impact of mitochondrial morphology on ischemia reperfusion injury and acute transplant rejection in vivo. Pre-treatment with mitochondrial fusion therapeutics will shift the current standard of care in transplantation.

摘要：器官移植是有机衰竭患者的主流疗法。但是，尽管如此该领域的重大进展，关于移植的两个主要组成部分几乎没有进步 - 器官保存和维护免疫抑制。虽然必不可少的免疫抑制治疗承担重大副作用负担，通常导致患者死亡和移植失败。另外，该过程器官采购的最常包括使用来自脑死供体的移植物，然后是低温保存存储解决方案中的器官。在这些事件中，器官中的内皮细胞（EC）同种异体移植物在免疫学上进行启动，然后受到再灌注的侮辱。早期受伤使EC倾向于不适当的抗原表现和慢性移植功能障碍的影响，包括移植血管病导致长期移植失败。低温保存改变了同种异体移植物又假设会改变EC的免疫原性，最终影响细胞功能结果。该级联的中心是线粒体在塑造免疫代谢中的作用面对冷缺血和再灌注损伤的同种异体移植环境。在这个建议中，我们第一次探索线粒体形态与免疫代谢之间的机械关系 EC及其在移植设置中的免疫原性。我们以自己的数据为基础来评估迫使线粒体超微结构变化对保存过程中EC免疫原性的影响移植阶段。我们建议，通过抑制EC的早期免疫原性作用，我们可以创建通过使用减少的免疫抑制方案，诱导同种异体耐受性的机会减少这些必要药物的有害后果。我们将采用科学前提通过改变其代谢核心将EC重新编程为更耐受的状态，使其诱导其能力同种异体T细胞的促炎性变化减少。使用临床相关的体内模型移植，我们预计改变EC线粒体将改善移植物的存活并消除病理与同种异移植排斥相关。使用我们的初步数据作为骨干，我们假设冷缺血通过改变线粒体形态来加剧EC的免疫原性能力和代谢谱导致同种异体损伤。此外，以以下目的，我们的目标是保护器官同种异体移植物和将EC偏向更耐受的表型。目的1。我们将确定器官保存期间线粒体形态的影响体外内皮细胞的免疫原性。目标2。我们旨在评估线粒体形态对缺血再灌注损伤的影响和体内急性移植排斥。线粒体融合疗法的预处理将改变当前的移植中护理标准。