Deconstructing B cell transplantation tolerance

解构B细胞移植耐受性

• 批准号: 10216969
• 负责人: Anita S Chong
• 金额: $ 54.93万
• 依托单位: UNIVERSITY OF CHICAGO
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216969
• 关键词: Acute; Affinity; Allograft Tolerance; Allografting; Antibodies; Antibody Formation; Antibody Response; Antigens; Autoimmunity; B-Lymphocytes; BCR gene; Binding; Biological Markers; Cell surface; Cells; Clinic; Clinical; Clinical Data; Complement; Data; Development; Diagnosis; Event; Flow Cytometry; Functional disorder; Goals; Graft Rejection; Helper-Inducer T-Lymphocyte; Hematopoietic; Human; IRF4 gene; Immune; Immunity; Immunoglobulin-Secreting Cells; Immunosuppression; Immunosuppressive Agents; Knowledge; Laboratories; Lead; Life; Link; Listeriosis; Maintenance; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Morbidity - disease rate; Mus; Peripheral; Phase; Recombinant Antibody; Regulatory T-Lymphocyte; Reporting; Resistance; SH2D1A gene; Specificity; T-Lymphocyte; TNFSF5 gene; Testing; Transgenic Organisms; Transplant Recipients; Transplantation; Transplantation Tolerance; adoptive B cell transfer; allograft rejection; antibody-mediated rejection; base; clinically relevant; congenic; cost; donor-specific antibody; end-stage organ failure; heart allograft; immunosuppressed; in vivo; insight; kidney allograft; liver transplantation; mouse model; new therapeutic target; novel; patient tolerability; prevent; response; restraint; reverse tolerance; side effect; stem; therapeutic target; vaccine development

Summary/Abstract Transplantation tolerance, a state in which immunosuppression can be stopped while grafts remain functional, is a major goal in clinical transplantation field as it promises to reduce side effects, costs and non-adherence consequences associated with the current need for life-long immunosuppression. Tolerance can be spontaneously achieved in rare recipients of kidney allografts and more frequently in liver transplant recipients. In some cases tolerance is stable, while in others the allografts eventually fail. Emerging data have led us to hypothesize that robust peripherally induced transplantation tolerance depends on multiple redundant cell- intrinsic and -extrinsic mechanisms to control alloreactive T and B cells. This proposal focuses of defining the mechanisms that control alloreactive B cells. This focus is based on considerable experimental and clinical data that donor-specific antibody (DSA) is an independent barrier to long-term graft acceptance, and clinical observation that the development of antibodies in tolerant patients leads ultimately to allograft rejection. Over the past few years, my laboratory has focused on tracing the fate of endogenous alloreactive B cells in transplantation rejection and tolerance. Here, we propose to build on our exciting preliminary observations made in a mouse model of cardiac allograft tolerance that donor-specific B cells are not completely deleted but acquire a cell-autonomous dysfunctional state that prevents their differentiation into antibody-secreting cells and that is resistant to T cell help. However, these tolerant cells are not completely inert and, remarkably, are able to suppress naïve B cells in a donor-specific manner. We propose to define the: Aim 1. in vivo cellular requirements for donor-reactive B cells to become intrinsically tolerant; Aim 2. mechanisms maintaining donor- specific B cell-intrinsic tolerance and preventing their development into antibody-secreting cells; Aim 3. Mechanisms and consequences of tolerant B cell-mediated suppression. We anticipate that the completion of these studies will provide insights into novel mechanisms that result in and maintain B cell tolerance, biomarkers that distinguish tolerant B cells from naïve or effector/memory B cells, and potential therapeutic targets for controlling allograft-specific antibody responses in transplant recipients.

摘要/摘要 移植耐受，一种可以停止免疫抑制而移植物保持功能的状态， 是临床移植领域的一个主要目标，因为它有望减少副作用、成本和不依从性 与当前终身免疫抑制的需要相关的后果。公差可以 在罕见的同种异体肾移植受者中自发实现，而在肝移植受者中更常见。 在某些情况下，耐受性是稳定的，而在其他情况下，同种异体移植物最终会失败。新兴数据引导我们 假设强大的外周诱导移植耐受取决于多个冗余细胞 控制同种异体反应性 T 细胞和 B 细胞的内在和外在机制。该提案的重点是定义 控制同种反应性 B 细胞的机制。这一重点基于大量的实验和临床 数据表明，供者特异性抗体（DSA）是长期移植物接受的独立障碍，并且临床 观察发现，耐受患者体内产生的抗体最终会导致同种异体移植排斥。超过 在过去的几年里，我的实验室一直致力于追踪内源性同种异体 B 细胞的命运 移植排斥和耐受。在这里，我们建议以我们令人兴奋的初步观察为基础 在心脏同种异体移植耐受的小鼠模型中发现，供体特异性 B 细胞并未完全删除，但 获得细胞自主功能障碍状态，阻止其分化为抗体分泌细胞 并且它对 T 细胞的帮助具有抵抗力。然而，这些耐受细胞并非完全惰性，而且值得注意的是， 能够以供体特异性方式抑制幼稚 B 细胞。我们建议定义： 目标 1. 体内细胞 供体反应性 B 细胞变得内在耐受的要求；目标 2. 维持捐助者的机制 特异性 B 细胞内在耐受性并阻止其发育成抗体分泌细胞；目标3。 耐受 B 细胞介导的抑制的机制和后果。我们预计完成 这些研究将深入了解导致和维持 B 细胞耐受性的新机制， 区分耐受性 B 细胞与初始或效应/记忆 B 细胞的生物标志物，以及潜在的治疗方法 控制移植受者中同种异体移植物特异性抗体反应的目标。