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：器官移植是器官衰竭患者的主流治疗方法。然而，尽管尽管该领域取得了重大进展，但移植的两个主要组成部分却进展甚微—— 器官保存和维持免疫抑制。免疫抑制治疗虽然必不可少具有显着的副作用负担，常常导致患者死亡和移植失败。此外，该过程器官获取最常包括使用脑死亡捐献者的移植物，然后是低温在储存溶液中保存器官。在这些事件期间，器官中的内皮细胞 (EC) 同种异体移植物经过免疫学引发，然后遭受再灌注的损害。这早期受伤使 EC 容易出现不适当的抗原呈递和慢性移植物功能障碍的影响，包括移植物血管病变导致长期移植失败。低温保存改变了新陈代谢同种异体移植，假设这反过来会改变 EC 的免疫原性，最终影响细胞功能结果。该级联的核心是线粒体在塑造免疫代谢中的作用同种异体移植物面临冷缺血和再灌注损伤的环境。在这项提案中，我们第一次，探讨线粒体形态与免疫代谢之间的机制关系 EC 及其在移植环境中的免疫原性。我们根据自己的数据来评估保存过程中强迫线粒体超微结构变化对 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，我们可以创造有机会通过减少免疫抑制方案来诱导同种异体移植耐受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 ECs 的代谢核心，将其重新编程至更耐受的状态，从而使其能够诱导同种异体反应性 T 细胞的促炎性变化减少。使用临床相关的体内模型移植后，我们预计改变 EC 线粒体将提高移植物存活率并消除病理学与同种异体移植排斥有关。使用我们的初步数据作为支柱，我们假设冷缺血通过改变线粒体形态来增强 EC 的免疫原性能力和代谢特征导致同种异体移植物损伤。此外，为了实现以下目标，我们的目标是保护器官同种异体移植物和使 EC 偏向于更耐受的表型。目标 1. 我们将确定器官保存过程中线粒体形态对内皮细胞的体外免疫原性。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反应。线粒体融合疗法的预处理将改变当前移植的护理标准。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Connexins in endothelial cells as a therapeutic target for solid organ transplantation.

内皮细胞中的连接蛋白作为实体器官移植的治疗靶点。

DOI：
发表时间：
2022-11
期刊：
影响因子：
0
作者：
Jaishankar, Dinesh;Quinn, Kristen M;Sanders, Jes;Plumblee, Leah;Morinelli, Thomas A;Nadig, Satish N
通讯作者：
Nadig, Satish N

Adoptive Transfer of Regulatory Immune Cells in Organ Transplantation.

器官移植中调节性免疫细胞的过继转移。