Exosome-mediated Tolerance in combined Kidney and Stem Cell Transplantation

肾和干细胞联合移植中外泌体介导的耐受性

• 批准号: 9809712
• 负责人: Jeremy A Sullivan
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809712
• 关键词: Abbreviations; Adult; Affinity; Alloantigen; Allogenic; Allografting; Antigens; Area; Autoimmune Diseases; B-Lymphocytes; Biological Markers; CD81 gene; Cell surface; Cells; Child; Chimerism; Chronic; Clinical; Clinical Trials; Complex; Confocal Microscopy; Dendritic Cells; Dialysis procedure; Dreams; Dual-role transvestism; Electron Microscopy; End stage renal failure; Enrollment; Failure; Flow Cytometry; Freedom; Future; Goals; Graft Rejection; Graft Survival; HLA Antigens; Haplotypes; Horseradish Peroxidase; Human; Image; Immune response; Immunohistochemistry; Immunologic Monitoring; Immunology procedure; Immunosuppressive Agents; Individual; Inherited; Kidney; Kidney Transplantation; Life; Lipids; Living Donors; Lymphatic Irradiation; Lymphocyte; Malignant Neoplasms; Mediating; Medicine; Membrane; MicroRNAs; Microchimerism; Monitor; Mothers; NIMA; Nucleic Acids; Organ failure; Outcome; PDCD1LG1 gene; Participant; Particle Size; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physicians; Price; Probability; Proteins; Protocols documentation; Regulation; Regulatory T-Lymphocyte; Role; Serum; Siblings; Site; Stem cell transplant; Stem cells; Sterile coverings; System; T-Lymphocyte; Testing; Tetanus Toxoid; Th1 Cells; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Transfusion; Transplant Recipients; Transplant Surgeon; Transplantation; Transplantation Tolerance; Universities; Virus; base; cohort; conditioning; exhaustion; exosome; extracellular; extracellular vesicles; follow-up; in utero; induced pluripotent stem cell; kidney cell; nanovesicle; neonate; peripheral tolerance; post-transplant; preconditioning; tumor; uptake

Abstract With the advent of mixed chimerism as a clinical transplantation tolerance strategy, understanding the mechanisms leading to stable tolerance has become critical. We now have evidence that a key component of transplant tolerance is provided by tiny, virus-sized particles called exosomes. Exosomes derived from Treg cells were not only critical to the mechanism of donor-specific transfusion (DST) co-stimulation (CoS) blockade-induced tolerance, but they may also be the basis of tolerance effects resulting from bi-directional regulation between host and living-related kidney donor . Besides Treg-derived exosomes, the recent discovery of a major role for exosomes from donor “passenger” DC (dendritic cells) in transplant rejection led us to test the hypothesis that DC exosomes could also do the opposite, i.e. promote transplant tolerance. We found that maternal DC microchimerism, resulting from the interaction of mother and child in utero and persisting in the neonate and throughout adult life, produce exosomes that amplify the tolerogenic impact of rare allogeneic cells. This discovery could finally explain the higher probability of graft survival in a transplant between siblings that differ for HLA at the non-inherited maternal haplotype. We propose, herein, a pilot immune monitoring study of: 1) normal HLA-identical and 1 haplotype mismatch living related donor (LRD) kidney transplants, and 2) the same patient-donor types, but enrolled in a combined total lymphoid irradiation (TLI)+ kidney/hematopoetic stem cell (HSC) transplantation trial at the UW-Madison. The goal of the trial would be to determine if monitoring of Treg- and DC-derived exosomes will predict which patients are successful, and which will fail to achieve tolerance. We hypothesize that in living-related donor-recipient pairs with pre-transplant “bi-directional regulation”, host and graft-resident Tregs will produce exosomes that cross-dressed bystander T & B cells with IL35, promoting infectious tolerance. Similarly, we hypothesize that DC exosomes capable of inducing PD-L1 expression in HLA-cross- dressed (XD) DC will correlate with excellent graft outcome. We predict that both of these positive exosome effects will be amplified in the context of RTx/TLI/HSC pre-conditioning. Failure to detect IL35 on LC exosomes, and PD-L1 miRs/lncRNAs within DC exosomes in successful tolerance induction will support a “null” hypothesis. Our goal is to discover the role of Treg- and DC-derived exosomes in a clinical tolerance trial.

摘要 随着混合嵌合体作为临床移植耐受策略的出现，理解 导致稳定容忍的机制已经变得至关重要。我们现在有证据表明， 移植耐受性是由病毒大小的微小颗粒提供的，这种颗粒被称为外体。Treg来源的外体 细胞不仅是供者特异性输血(DST)共刺激(CoS)机制的关键。 封锁诱导的耐受性，但它们也可能是双向耐受性效应的基础 宿主与活体亲属肾捐献者之间的规范。除了Treg衍生的外切体，最近的 发现供者DC(树突状细胞)外切体在移植排斥反应中的主要作用 我们来验证DC外切体也可以做相反的事情，即促进移植耐受的假说。我们 发现母体DC微嵌合体，由母子在宫内和宫内的相互作用引起 在新生儿和整个成年生活中坚持，产生外体，放大耐受性影响 罕见的同种异体细胞。这一发现最终可以解释移植后移植物存活率较高的原因。 在非遗传性母体单倍型上具有不同的人类白细胞抗原的兄弟姐妹之间。在此，我们建议一名飞行员 1)正常人类白细胞抗原相合和1例半相合活体亲属供者的免疫监测研究 肾移植，以及2)相同的患者-供者类型，但登记参加联合全淋巴照射 (TLI)+肾脏/造血干细胞(HSC)移植试验在威斯康星大学麦迪逊分校进行。试验的目的是 将确定监测Treg和DC来源的外切体是否可以预测哪些患者 成功，而这将无法实现宽容。我们假设，在活体亲属捐赠者-接受者中 配对移植前“双向调节”，宿主和移植物驻留的Treg将产生 外体使旁观者T&B细胞与IL35交叉穿衣，促进感染耐受性。 类似地，我们假设DC外切体能够诱导PD-L1在HLA-cross-L1中的表达。 穿着的(XD)DC与良好的移植物效果相关。我们预测，这两个积极因素 Exosome效应将在RTX/TLI/HSC预适应的背景下被放大。未能在LC上检测到IL35 Exosome和DC Exosome内的PD-L1miRs/lncRNAs成功诱导耐受将支持 “零”假设。我们的目标是发现Treg和DC来源的外切体在临床耐受中的作用 审判。