Immunologic Biomarkers of Rejection in Clinical Liver Transplantation

临床肝移植​​排斥反应的免疫生物标志物

• 批准号: 10412948
• 负责人: Juliet Emamaullee
• 金额: $ 26.69万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412948
• 关键词: Acute; Address; Advisory Committees; Aftercare; Allografting; Antibodies; Autoimmune Hepatitis; Award; Bioinformatics; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Blood specimen; California; Career Mobility; Cells; Chronic; Clinical; Clinical Trials; Core Biopsy; Cytometry; Data; Data Analyses; Development; Development Plans; Diagnosis; Disease; Enrollment; Ensure; Failure; Funding; Future; Goals; Graft Rejection; Grant; Hepatoblastoma; Histologic; Hospitals; Human; Image; Immune; Immune response; Immunohistochemistry; Immunologic Markers; Immunologic Techniques; Immunologics; Immunology; Immunosuppression; Kidney Transplantation; Knowledge; Laboratories; Learning; Liver; Liver Function Tests; Liver parenchyma; Los Angeles; Lymphocyte; Lymphocyte Subset; Maps; Measures; Mediating; Mentors; Mentorship; Methods; Mission; Molecular Analysis; Operative Surgical Procedures; Organ Transplantation; Outcome; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Peripheral Blood Mononuclear Cell; Phase; Population; Primary carcinoma of the liver cells; Process; Protocols documentation; Public Health; Research; Research Design; Research Personnel; Research Project Grants; Resources; Schedule; Severities; Solid; Specimen; Stains; Strategic Planning; Techniques; Therapeutic; Time; Tissue Sample; Tissue Transplantation; Tissues; Training; Translational Research; Transplant Recipients; Transplant Surgeon; Transplantation Immunology; Tumor-infiltrating immune cells; United States National Institutes of Health; Universities; Withdrawal; Woman; Work; allograft rejection; base; career development; clinical care; clinically relevant; complex data; ethnic minority; experimental study; hands-on learning; human subject; improved; individual patient; intrahepatic; isoimmunity; liver biopsy; liver injury; liver transplantation; novel; novel diagnostics; novel marker; peripheral blood; post-transplant; primary sclerosing cholangitis; professor; prospective; skills; spatial relationship; tool

PROJECT SUMMARY Candidate: Juliet Emamaullee is an Assistant Professor of Clinical Surgery at the University of Southern California (USC) and an attending liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital- Los Angeles. Dr. Emamaullee has been working with her proposed K08 mentor, Dr. Omid Akbari, and her co- mentor, Dr. Shahab Asgharzadeh, to learn about mass cytometry approaches to characterize immune responses and now has begun independent work to develop these techniques to analyze the process of rejection in liver transplant (LT) recipients. The project aims to provide her with additional skills and knowledge required to achieve her long-term goal of studying the immunologic mechanisms involved in development and progression of LT rejection in order to develop new diagnostic, preventative, and therapeutic approaches to improve post-LT outcomes. Career Development Plan: Dr. Emamaullee has strategically planned to gain the necessary training and mentoring that will be required for her successful transition to being an independent investigator through select coursework and a robust mentoring plan. She has also organized an advisory committee composed not only of leaders in the field but also those able to directly impact her career advancement. The immediate training objectives are focused on consolidating her expertise in: (1) advanced immunological techniques including mass cytometry; (2) bioinformatics and data analysis; and (3) immunological pathways of rejection in clinical LT. This will not only ensure that Dr. Emamaullee's research project progresses as planned but will also ensure her progress will be recognized through promotion and obtaining independent research funding. She has an impactful, unique research project that is sufficiently different from her mentor's research to avoid competition or overlap. Research Plan: The proposed study leverages the extensive resources available at USC to address an important public health issue, which makes it directly relevant to the NIH mission. Hepatocellular carcinoma is on pace to become the leading global indication for LT, and rejection continues to be an important cause of graft loss and failure post-transplant. The diagnosis of rejection is not correlative to changes in liver blood tests and thus requires an invasive biopsy. Recently, there have been significant advances in the sensitivity of techniques to characterize immune responses, even in small tissue samples. We hypothesize that a liver-focused immune panel can be developed using imaging mass cytometry (IMC) to deeply analyze intrahepatic immune infiltrates in human liver tissue. We also hypothesize that graft-infiltrating lymphocytes can be characterized using IMC to better understand which subpopulations mediate allograft rejection in LT. First, we will develop a Liver Immunology IMC Panel using tissue obtained from LT patients with chronic rejection. Furthermore, we will utilize this assay to characterize graft-infiltrating lymphocyte subpopulations in chronic rejection and compare to results obtain using tissue obtained from LT patients with acute rejection. Immune profiles in each phase of rejection will be quantified and mapped, as well as compared to clinical parameters. Lastly, we will study LT patients prospectively to determine if these rejection-associated lymphocytes can be tracked in the blood during and after episodes of rejection. This project represents the first application of IMC in solid organ transplantation and has the potential to expand our knowledge of alloimmunity in clinical LT, which could provide the basis for a noninvasive assay of rejection in LT patients.

项目摘要 候选人：朱丽叶Emamaullee是南部大学临床手术的助理教授 加利福尼亚州（USC）以及凯克医院和儿童医院的肝脏和肾脏移植外科医生 洛杉矶。 Emamaullee博士一直与她的拟议的K08导师Omid Akbari博士一起工作，她的共同 导师Shahab Asgharzadeh博士，了解质量细胞术方法以表征免疫反应 现在已经开始独立的工作来开发这些技术，以分析肝脏中排斥的过程 移植（LT）受体。该项目旨在为她提供所需的其他技能和知识 实现她研究与发展和发展有关的免疫机制的长期目标 LT拒绝的目的是为了开发新的诊断，预防和治疗方法来改善LT 结果。 职业发展计划：Emamaullee博士已战略计划，以获得必要的培训和 通过SELECT成功过渡到成为独立调查员需要的指导 课程工作和强大的心理计划。她还组织了一个咨询委员会，不仅由 该领域的领导者，也能够直接影响她的职业发展。即时培训 目标的重点是巩固她的专业知识：（1）包括质量在内的先进免疫技术 细胞仪； （2）生物信息学和数据分析； （3）临床LT中排斥反应的免疫学途径。这 不仅将确保Emamaullee博士的研究项目按计划进行，还将确保她 进步将通过晋升和获得独立的研究资金来确认。她有一个 有影响力的独特研究项目与她的心理研究完全不同，以避免竞争或 重叠。 研究计划：拟议的研究利用了USC可用的广泛资源来解决重要的 公共卫生问题，这使其与NIH任务直接相关。肝细胞癌正在空间 成为LT的主要全球迹象，拒绝仍然是移植物损失和 移植后失败。排斥反应的诊断与肝血液检查的变化无关，因此 需要侵入性活检。最近，技术对技术的敏感性取得了重大进步 即使在小组织样品中，也可以表征免疫调查。我们假设以肝脏为中心的免疫回报 可以使用成像质量细胞仪（IMC）开发面板，以深入分析ePatitic脑内免疫浸润 在人肝组织中。我们还假设可以使用IMC TO将移植浸入淋巴细胞进行表征 更好地了解哪些亚群介导LT中的同种异体移植排斥。首先，我们将发展肝脏 免疫学IMC面板使用从慢性排斥的LT患者获得的组织。此外，我们将使用 该测定法表征了慢性排斥的淋巴细胞亚群，并与结果进行比较 使用从急性排斥的LT患者获得的组织获得。在拒绝阶段的每个阶段的免疫特征 将被量化和映射，并与临床参数相比。最后，我们将研究LT患者 前瞻性确定这些反应相关的淋巴细胞是否可以在血液中和之后的血液中进行跟踪 拒绝情节。该项目代表了IMC在实体器官移植中的第一个应用，并且具有 扩展我们对临床LT中同种免疫知识的了解的潜力，这可以为A提供基础 LT患者对排斥反应的无创评估。