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: 10634536
• 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/10634536
• 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; Infiltration; 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; United States National Institutes of Health; Universities; Withdrawal; Woman; Work; allograft rejection; career development; clinical care; clinically relevant; complex data; ethnic minority; experimental study; hands-on learning; human subject; immune cell infiltrate; 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.

项目概要 候选人：Juliet Emamaullee 是南方大学临床外科助理教授 加利福尼亚州（南加州大学）以及凯克医院和儿童医院的肝肾移植主治外科医生 - 洛杉矶。 Emamaullee 博士一直在与她提议的 K08 导师 Omid Akbari 博士以及她的同事合作 导师 Shahab Asgharzadeh 博士，了解表征免疫反应的质谱流式细胞术方法 现在已经开始独立工作来开发这些技术来分析肝脏的排斥过程 移植（LT）受者。该项目旨在为她提供所需的额外技能和知识 实现她研究发育和进展中涉及的免疫机制的长期目标 LT 排斥反应，以开发新的诊断、预防和治疗方法来改善 LT 后的情况 结果。 职业发展计划：Emaullee 博士已战略性地计划获得必要的培训和 她通过选择成功过渡为独立调查员所需的指导 课程作业和强大的指导计划。她还组织了一个咨询委员会，其成员不仅包括 该领域的领导者，但也包括那些能够直接影响她的职业发展的人。立即培训 目标集中于巩固她在以下方面的专业知识：（1）先进的免疫学技术，包括质谱 细胞计数术； (2)生物信息学和数据分析； (3) 临床 LT 排斥反应的免疫学途径。这 不仅将确保Emaullee博士的研究项目按计划进行，还将确保她 进步将通过推广和获得独立研究经费得到认可。她有一个 有影响力、独特的研究项目，与她导师的研究有很大不同，以避免竞争或 重叠。 研究计划：拟议的研究利用南加州大学现有的广泛资源来解决一个重要问题 公共卫生问题，这使得它与 NIH 的使命直接相关。肝细胞癌正在加速发展 成为 LT 的全球主要适应症，排斥反应仍然是移植物损失和移植物丢失的重要原因 移植后失败。排斥反应的诊断与肝脏血液检查的变化无关，因此 需要进行侵入性活检。最近，技术的敏感性有了显着的进步。 即使在小组织样本中也能表征免疫反应。我们假设以肝脏为中心的免疫 可以使用成像质量流式细胞仪 (IMC) 开发面板来深入分析肝内免疫浸润 在人体肝脏组织中。我们还假设可以使用 IMC 来表征移植物浸润淋巴细胞 更好地了解哪些亚群介导 LT 中的同种异体移植排斥反应。首先，我们要开发一个肝脏 免疫学 IMC Panel 使用从患有慢性排斥反应的 LT 患者获得的组织。此外，我们将利用 该测定可表征慢性排斥反应中的移植物浸润淋巴细胞亚群并与结果进行比较 使用取自患有急性排斥反应的 LT 患者的组织来获得。排斥反应各阶段的免疫特征 将被量化和绘制，并与临床参数进行比较。最后，我们将研究 LT 患者 前瞻性地确定这些与排斥相关的淋巴细胞是否可以在治疗期间和治疗后在血液中进行追踪 拒绝的情节。该项目是IMC在实体器官移植领域的首次应用， 扩大我们对临床 LT 中同种免疫的了解的潜力，这可以为 LT 患者排斥反应的无创测定。

项目成果

Adaptation of Imaging Mass Cytometry to Explore the Single Cell Alloimmune Landscape of Liver Transplant Rejection.

• DOI: 10.3389/fimmu.2022.831103
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Revisiting transplant immunology through the lens of single-cell technologies.

• DOI: 10.1007/s00281-022-00958-0
• 发表时间: 2023-01
• 期刊: SEMINARS IN IMMUNOPATHOLOGY
• 影响因子: 9
• 作者: Barbetta, Arianna;Rocque, Brittany;Sarode, Deepika;Bartlett, Johanna Ascher;Emamaullee, Juliet
• 通讯作者: Emamaullee, Juliet

New Approaches to the Diagnosis of Rejection and Prediction of Tolerance in Liver Transplantation.

• DOI: 10.1097/tp.0000000000004160
• 发表时间: 2022-10-01
• 期刊: Transplantation
• 影响因子: 6.2

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

• DOI: 10.1002/lt.26399
• 发表时间: 2022-05
• 期刊: LIVER TRANSPLANTATION
• 影响因子: 4.6
• 作者: Rocque, Brittany;Zaldana, Aaron;Weaver, Carly;Huang, Julia;Barbetta, Arianna;Shakhin, Victoria;Goldbeck, Cameron;Yanni, George;Zielsdorf, Shannon;Kwon, Yong;Etesami, Kambiz;Genyk, Yuri;Zhou, Shengmei;Kohli, Rohit;Emamaullee, Juliet
• 通讯作者: Emamaullee, Juliet

Treatment and outcomes of hepatocellular carcinoma in patients with Sickle cell disease: a population-based study in the U.S.

• DOI: 10.1016/j.hpb.2021.06.420
• 发表时间: 2022-03
• 期刊: HPB : the official journal of the International Hepato Pancreato Biliary Association
• 作者: Barbetta A;Goldbeck C;Lim A;Martin SP;Kahn JA;Sheikh MR;Emamaullee J
• 通讯作者: Emamaullee J