Imaging of Cardiac Transplant Rejection

心脏移植排斥的影像学

基本信息

批准号：
8496096
负责人：
Matthias Nahrendorf
金额：
$ 41.58万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496096
关键词：
Adoptive Cell Transfers Adoptive Transfer Adrenal Cortex Hormones Allografting Antimetabolites Atherosclerosis Benchmarking Biological Biological Markers Biopsy Bone Marrow Calcineurin inhibitor Cardiac Chimerism Clinical Clinical Trials Complication Cysteine Protease Development Diagnostic Disease Exhibits Functional disorder Goals Gold Graft Rejection Graft Survival Health Heart Heart Diseases Heart Transplantation Histology Image Imaging Device Immune system Immunity Immunosuppressive Agents Individual Inflammation Inflammatory Isogenic transplantation Label Longitudinal Studies Lymphocyte Magnetic Resonance Imaging Modeling Molecular Molecular Target Monitor Mus Myocardial Optics Organ Patients Peroxidases Phagocytosis Play Population Prodrugs Recruitment Activity Regimen Reporter Research Risk Role Sampling Errors Sensitivity and Specificity Staging Steroids Survival Rate T-Lymphocyte Testing Therapeutic Therapeutic immunosuppression Time Transplantation Treatment Protocols allograft rejection base cohort comparative cytokine heart allograft imaging modality improved in vivo insight kidney allograft macrophage molecular imaging monocyte nanoparticle repaired sensor tool wound

项目摘要

DESCRIPTION (provided by applicant): Heart transplantation is often the only available therapeutic option in end-stage heart disease. To monitor graft survival, recipients endure frequent invasive endomyocardial biopsies which carry a significant risk of complication and are prone to sampling-errors. There is thus a compelling need to develop noninvasive, more predictive and quantitative diagnostic tools to monitor individual patients and to compare new treatment regimen in different patient cohorts. An increasing body of work suggests that macrophages are highly abundant in rejected allografts, and exhibit cardinal cellular and molecular functions. The overall goal of this proposal is to evaluate macrophages and macrophage-associated functions as in vivo imaging biomarkers of transplant rejection. Specifically, we will validate a) nanoparticles as reporters of phagocytic activity, b) optical prodrugs as sensors of cysteine protease activity, and c) myeloperoxidase-targeted magnetic resonance imaging agents. We will investigate which of the above imaging marker correlates most closely with the ex vivo gold standard (ISHLT-graded histology) and CD68 expression and if imaging can detect earliest forms of rejection and/or tolerance at sufficiently high sensitivity and specificity. We will test these MU-targeted cardiac imaging tools to non-invasively investigate 3 specific therapeutic approaches to treat transplant rejection. First we will benchmark macrophage imaging during the use of routine immunosuppressants (calcineurin inhibitor, antimetabolite agent and corticosteroids). Next we will investigate emerging tolerance regimen (induction of mixed chimerism by bone marrow co- transplantation). Finally, we will use mice deficient for macrophage recruiting cytokines and adoptive cell transfer to reprogram prevalent macrophage populations in the heart from the inflammatory M1 to reparative M2 subsets. These longitudinal studies will be used to validate functional macrophage-targeted agents for noninvasive heart transplant imaging.

描述（由申请人提供）：心脏移植通常是末期心脏病中唯一可用的治疗选择。为了监测移植物的存活，接受者忍受了频繁的侵入性内膜活检，这些活检具有显着的并发症风险，并且容易出现采样。因此，迫切需要开发无创，更具预测性和定量的诊断工具来监测单个患者并比较不同患者同类的新治疗方案。越来越多的工作表明，巨噬细胞在被拒绝的同种异体移植物中高度丰富，并且表现出主要的细胞和分子功能。该提案的总体目标是评估巨噬细胞和巨噬细胞相关的功能，作为移植排斥的体内成像生物标志物。具体而言，我们将验证a）纳米颗粒作为吞噬活性的记者，b）光前药作为半胱氨酸蛋白酶活性的传感器，以及c）骨过氧化物酶靶向的磁共振成像剂。我们将研究上述哪些标记物中的哪种与体内金标准（ISHLT级的组织学）和CD68表达最紧密相关，以及是否可以在足够高灵敏度和特异性下检测最早的排斥和/或公差形式。我们将测试这些靶向MU的心脏成像工具，以非侵入性研究3种特定的治疗方法来治疗移植排斥反应。首先，我们将在使用常规免疫抑制剂（钙调蛋白抑制剂，抗代谢剂和皮质类固醇）期间基准基准巨噬细胞成像。接下来，我们将研究新兴的耐受性方案（通过骨髓合作诱导混合嵌合体的诱导）。最后，我们将使用缺乏巨噬细胞募集细胞因子和收养细胞转移的小鼠来重新编程，从炎症M1到修复M2子集的心脏中流行的巨噬细胞种群。这些纵向研究将用于验证功能性巨噬细胞靶向的剂进行非侵入性心脏移植成像。