B Cells in Tolerance and Chronic Rejection of Monkey Kidney Allografts

B 细胞对猴肾同种异体移植物的耐受性和慢性排斥

• 批准号: 9244900
• 负责人: GILLES A BENICHOU
• 金额: $ 25.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244900
• 关键词: Allogenic; Allograft Tolerance; Allografting; Animals; Antibodies; B-Lymphocyte Subsets; B-Lymphocytes; Blood; Bone Marrow; Bone Marrow Cells; CD19 gene; CD8B1 gene; Cellular biology; Chimerism; Chronic; Clinical; Clinical Immunology; Cytokine Gene; Evaluation; Fibrosis; Frequencies; Graft Rejection; Graft Survival; Graft Tolerance; Hematopoietic; Human; Immune Tolerance; Immunosuppression; Inflammation; Infusion procedures; Isoantibodies; Kidney; Kidney Transplantation; Leukocytes; Link; Longitudinal Studies; Lymphoid; MS4A1 gene; Macaca fascicularis; Maintenance; Measures; Molecular Profiling; Monkeys; Mus; Nature; Organ; Patients; Phenotype; Play; Population; Procedures; Process; Production; Property; Research; Role; Sampling; Series; Spleen; Testing; Time; Transplantation; Withdrawal; Work; allograft rejection; conditioning; cytokine; design; effective therapy; genetic signature; kidney allograft; lymph nodes; novel; peripheral blood; prevent; safety and feasibility; sample collection; transcriptome sequencing

PROJECT SUMMARY / ABSTRACT Transient mixed hematopoietic chimerism and long-term survival of kidney allografts in the absence of immunosuppression has been achieved in monkeys and patients via non-myeloablative conditioning, infusion of donor bone marrow cells and short-term leukocyte costimulation blockade. However, a significant proportion of monkey kidney allografts (50%) undergoing long-term survival display features of chronic rejection (CR) within one year post-transplantation, a phenomenon also observed among many patients treated with a similar procedure at MGH. Recently, B cells have been implicated in both transplant rejection and tolerance. However, the nature of the B cells involved in these processes and their mechanisms of action are still unclear. Our proposed research will use a large collection of specimens (from blood and lymphoid organs) to characterize the phenotype as well as cytokine and gene expression profiles of the B cell subsets involved in chronic rejection vs. tolerance of kidney allografts in monkeys treated with our mixed chimerism procedure. In addition, we have recently identified a novel population of B cells in monkeys (and humans), which are CD19+ CD20+ BCR+ and unexpectedly CD8+. Most importantly, preliminary studies show an expansion of these unconventional B cells in the peripheral blood of chimeric monkeys, which became tolerant. To our knowledge, the nature, functions and association with tolerance of these B cells have never been investigated. Further characterization of the phenotype, cytokine signatures and regulatory properties of newly discovered CD8+ B cells (found in monkeys and humans) and evaluation of their association with immune tolerance has potential implications both in basic and clinical immunology Specific aim 1. To identify B cell subsets and signatures involved in chronic rejection vs. tolerance of kidney allografts. Specific Aim 2. To further characterize newly described CD8+ B lymphocytes and investigate their relationships with tolerance In addition to the theoretical implications of the work related to basic B cell biology, identification of the B cell subsets and signatures of transplant tolerance will enhance the safety and feasibility of clinical tolerance trials and facilitate management of patients receiving immunosuppression.

项目概要/摘要 短暂混合造血嵌合和同种异体肾移植物在缺乏的情况下的长期存活 通过非清髓性调理、输注在猴子和患者中实现了免疫抑制 供体骨髓细胞和短期白细胞共刺激阻断。然而，有相当大的比例 经历长期存活的猴肾同种异体移植物（50%）显示出慢性排斥（CR）的特征 在移植后一年内，在许多接受类似治疗的患者中也观察到了这种现象 MGH 的手术。最近，B 细胞与移植排斥和耐受有关。然而， 参与这些过程的 B 细胞的性质及其作用机制仍不清楚。 我们提议的研究将使用大量标本（来自血液和淋巴器官）来 表征参与 B 细胞亚群的表型以及细胞因子和基因表达谱 用我们的混合嵌合程序治疗的猴子的同种异体肾移植物的慢性排斥与耐受性。 此外，我们最近在猴子（和人类）中发现了一个新的 B 细胞群，它们是 CD19+ CD20+ BCR+ 和意外的 CD8+。最重要的是，初步研究表明 嵌合猴外周血中的这些非常规 B 细胞变得耐受。致我们的 这些 B 细胞的知识、性质、功能及其与耐受性的关系从未被研究过。 新发现的表型、细胞因子特征和调控特性的进一步表征 CD8+ B 细胞（在猴子和人类中发现）及其与免疫耐受性的关联评估 对基础和临床免疫学的潜在影响 具体目标 1. 鉴定参与慢性排斥与耐受的 B 细胞亚群和特征 同种异体肾移植物。 具体目标 2. 进一步表征新描述的 CD8+ B 淋巴细胞并研究其 宽容的关系 除了与基础 B 细胞生物学相关的工作的理论意义外，B 细胞的鉴定 移植耐受的子集和特征将提高临床耐受试验的安全性和可行性 并促进接受免疫抑制患者的管理。