Targeting Donor Regulatory Dendritic Cells During Normothermic Ex Vivo Liver Perfusion to Overcome Rejection after Liver Transplant

在常温离体肝脏灌注过程中靶向供体调节树突状细胞以克服肝移植后的排斥反应

• 批准号: 10630330
• 负责人: David Peter Al-Adra
• 金额: $ 19.79万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-07 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630330
• 关键词: Acute; Affect; Animals; Anti-Inflammatory Agents; Belief; Biology; Biometry; Cells; Cellular biology; Clinical; Communication; Competence; Dangerousness; Data; Dedications; Dendritic Cells; Development; Educational Activities; Environment; Ethics; Flow Cytometry; Foundations; Frequencies; Goals; Graft Rejection; Graft Survival; Immune; Immune response; Immune system; Immunologics; In Vitro; Inbred BN Rats; Infection; Interleukin-10; Intervention; Knowledge; Laboratories; Laboratory Research; Life; Liver; Malignant Neoplasms; Measures; Mediating; Mentorship; Methods; Modeling; Modification; Operative Surgical Procedures; Organ; Organ Donor; Organ Transplantation; Outcome; Patients; Perfusion; Pharmaceutical Preparations; Phenotype; Physiological; Production; Program Development; Property; Proteins; Rattus; Reaction; Research; Research Design; Research Personnel; Risk; Role; Scientist; Solid; Surgeon; Techniques; Technology; Testing; Time; Training; Transforming Growth Factor beta; Translating; Transplant Recipients; Transplantation; Transplantation Immunology; Transplantation Surgery; Universities; Wisconsin; anti-PD-L1 antibodies; career; career development; clinical practice; clinically relevant; cytokine; cytokine therapy; end stage liver disease; experience; extracellular vesicles; immune checkpoint; immunoreaction; immunoregulation; improved; in vivo; innovation; liver function; liver transplantation; novel; organ transplant rejection; professor; programmed cell death ligand 1; public health relevance; response; side effect; skills; transplant model; tumor-immune system interactions

ABSTRACT This proposal presents a five-year research career development program focused on targeting donor liver- resident cells with regulatory properties to decrease rejection after transplantation. I am an Assistant Professor of Surgery at the University of Wisconsin-Madison, with previous research and clinical experience in transplant immunology and transplant surgery involving normothermic ex vivo machine perfusion (NEVLP), whereby an organ is housed under physiologic conditions. The present project will advance the field of transplant immunology by using NEVLP technology to modify the immune cells within the liver prior to transplantation. I have assembled an outstanding mentorship team of investigators with expertise in transplant immunology, dendritic cell biology, and extracellular vesicle biology. The proposed training will guide and enhance my development in core competencies, including transplant immunology, communication, biostatistics, and ethical research design that will enable me to transition to research independence as a surgeon-scientist dedicated to reducing organ rejection in the field of transplant surgery. Liver transplantation is the only treatment option for patients with end-stage liver disease; however, rejection of the transplant can decrease liver and patient survival. In addition, patients still require lifelong use of anti-rejection medications that suppress the immune system. Modification of the donor liver, and the immune cells within it, has the potential to promote acceptance of the liver and minimize the need for anti-rejection drugs. Advances in an innovative technique called normothermic ex vivo liver perfusion (NEVLP) offer a unique opportunity to benefit significantly the 25% of liver transplant recipients that develop acute rejection, as well as many more transplant recipients who would benefit from using fewer anti-rejection drugs. Recent studies have demonstrated the importance of regulatory dendritic cells (DCregs) for prolonging transplant survival. My central hypothesis is that expansion of the number of liver-resident DCregs during NEVLP will promote a regulatory environment for the organ after transplant. Using a rat model of NEVLP and liver transplantation that my research group has optimized, I expect NEVLP to expand DCregs potently, leading to an increase in immune checkpoint molecule expression and production of anti-inflammatory extracellular vesicles and cytokines that can reduce immune-mediated rejection. This innovative approach of expanding graft-resident DCregs to decrease rejection could be used in deceased donor liver transplantation as well as translated to other types of solid organ transplants. To achieve these objectives, I propose the following scientific aims: 1) Determine the dominant regulatory function of liver-resident DCregs after NEVLP, and 2) Measure the impact of expanded liver-resident DCregs generated by combination cytokine therapy during NEVLP on liver graft rejection in vitro and in vivo.

抽象的 该提案提出了一个为期五年的研究职业发展计划，重点关注捐赠肝脏 具有调节特性的常驻细胞可减少移植后的排斥反应。我是助理教授 威斯康星大学麦迪逊分校外科博士，拥有移植方面的先前研究和临床经验 涉及常温离体机器灌注（NEVLP）的免疫学和移植手术，其中 器官处于生理条件下。目前的项目将推动移植领域的发展 免疫学，在移植前使用 NEVLP 技术修改肝脏内的免疫细胞。我 组建了一支由具有移植免疫学专业知识的优秀研究人员组成的指导团队， 树突状细胞生物学和细胞外囊泡生物学。拟议的培训将指导和提高我的 核心能力的发展，包括移植免疫学、沟通、生物统计学和伦理学 研究设计将使我能够作为一名致力于研究的外科医生科学家过渡到研究独立性 减少移植手术领域的器官排斥。 肝移植是终末期肝病患者唯一的治疗选择；然而， 移植排斥会降低肝脏和患者的存活率。此外，患者仍需终生使用 抑制免疫系统的抗排斥药物。供体肝脏的修饰和免疫 其中的细胞，有可能促进肝脏的接受并最大限度地减少抗排斥的需要 药物。常温离体肝脏灌注 (NEVLP) 创新技术的进步提供了独特的方法 使 25% 出现急性排斥反应的肝移植受者受益的机会，以及 更多的移植受者将受益于使用更少的抗排斥药物。最近的研究有 证明了调节性树突状细胞（DCregs）对于延长移植物存活的重要性。我的 中心假设是 NEVLP 期间肝脏驻留 DCreg 数量的增加将促进 移植后器官的调节环境。使用 NEVLP 和肝移植大鼠模型 我的研究小组已经优化了，我预计 NEVLP 能够有效地扩展 DCregs，从而导致 免疫检查点分子的表达和抗炎细胞外囊泡的产生和 可以减少免疫介导的排斥反应的细胞因子。这种扩大移植驻地的创新方法 减少排斥反应的 DCregs 可用于死者供体肝移植，并转化为 其他类型的实体器官移植。为了实现这些目标，我提出以下科学目标： 1) 确定 NEVLP 后肝脏驻留 DCregs 的主要调节功能，以及 2) 测量 NEVLP 期间联合细胞因子治疗产生的扩大的肝脏驻留 DCregs 对肝脏的影响 体外和体内移植排斥。

项目成果

A master surgical educator: the "intrinsic" factor of Dr. Paul Greig.

• DOI: 10.1016/j.hpb.2022.07.014
• 发表时间: 2022-11
• 期刊: HPB
• 影响因子: 2.9
• 作者: Al-Adra, David P.;Barbas, Andrew S.;Shah, Shimul;Molinari, Michele
• 通讯作者: Molinari, Michele

The Immunological Effect of Oxygen Carriers on Normothermic Ex Vivo Liver Perfusion.

• DOI: 10.3389/fimmu.2022.833243
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Blood products and liver transplantation: A strategy to balance optimal preparation with effective blood stewardship.

• DOI: 10.1111/trf.17074
• 发表时间: 2022-10
• 期刊: TRANSFUSION
• 影响因子: 2.9
• 作者: Little, Christopher J.;Leverson, Glen E.;Hammel, Laura L.;Connor, Joseph P.;Al-Adra, David P.
• 通讯作者: Al-Adra, David P.