Immunologic Biomarkers of Rejection in Clinical Liver Transplantation

项目总结 候选人：Juliet Emamaullee是南方大学临床外科助理教授 加州(南加州大学)和凯克医院和儿童医院的肝肾移植主治医生- 洛杉矶。Emamaullee博士一直在与她推荐的K08导师奥米德·阿克巴里博士和她的同事-- 导师，Shahab Asgharzadeh博士，了解用于表征免疫反应的质量细胞术方法 现在已经开始了独立的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所涉及的免疫机制的长期目标 为了开发新的诊断、预防和治疗方法来改善移植后的排斥反应 结果。 职业发展计划：Emamaullee博士有战略地计划获得必要的培训和 她通过SELECT成功过渡到独立调查员所需的指导 课程作业和健全的指导计划。她还组织了一个咨询委员会，成员不仅包括 不仅是该领域的领导者，还包括那些能够直接影响她职业发展的人。立即进行的培训 目标集中于巩固她在以下方面的专业知识：(1)先进的免疫技术，包括质量 细胞学；(2)生物信息学和数据分析；(3)临床移植排斥反应的免疫学途径。这 将不仅确保Emamaullee博士的研究项目按计划进行，而且还将确保她 将通过促进和获得独立研究资金来确认进展。她有一个 有影响力的、独特的研究项目，与她导师的研究有很大的不同，以避免竞争或 重叠。 研究计划：拟议的研究利用南加州大学的广泛资源来解决一个重要的问题 公共卫生问题，这使得它与NIH的任务直接相关。肝细胞癌正在向 成为全球领先的肝移植适应症，排斥反应仍然是移植物丢失和 移植后失败。排异反应的诊断与肝脏血液检测的变化无关，因此 需要进行侵入性活组织检查。最近，在技术敏感性方面取得了重大进展。 表征免疫反应，即使是在小组织样本中也是如此。我们假设一种以肝脏为中心的免疫 可以使用成像质量细胞术(IMC)开发面板来深入分析肝内免疫浸润物 在人类肝组织中。我们还假设移植物浸润性淋巴细胞可以用IMC来表征 更好地了解哪些亚群参与了同种异体移植排斥反应的调节。首先，我们将开发一个肝脏 免疫学IMC小组使用来自慢性排斥的肝移植患者的组织。此外，我们将利用 本实验对慢性排斥反应中移植物浸润性淋巴细胞亚群进行了表征，并与结果进行了比较 取自急性排斥的肝移植患者的组织。排斥反应各阶段的免疫学特征 将被量化和绘制地图，并与临床参数进行比较。最后，我们将研究LT患者 前瞻性地确定是否可以在血液中追踪到这些排斥反应相关的淋巴细胞 一次次的拒绝。该项目是IMC在实体器官移植中的首次应用，并已 在临床移植中扩大我们对同种异体免疫的知识的潜力，这可能为 肝移植患者排异反应的无创性检测。

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.