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 移植耐受性，即可以在移植物保持功能时停止免疫抑制的状态， 是临床移植场的主要目标，因为它有望降低副作用，成本和不遵守 与当前对终身免疫抑制的需求相关的后果。宽容可以 在罕见的肾脏合物接受者中获得赞助，在肝移植受者中更频繁地实现。 在某些情况下，公差是稳定的，而在其他情况下，同类最终会失败。新兴数据使我们进入 假设强大的定期诱导移植耐受性取决于多个冗余细胞 - 固有的和 - 控制的机制，以控制同种反应性T和B细胞。该建议重点是定义 控制同种异体B细胞的机制。此重点基于考虑实验和临床 供体特异性抗体（DSA）的数据是长期接枝接受和临床的独立障碍 观察到耐受患者的抗体的发展最终导致同种异体移植排斥。超过 在过去的几年中，我的实验室重点是追踪内源性同种异体B细胞的命运 移植排斥和公差。在这里，我们建议以我们令人兴奋的初步观察为基础 在供体特异性B细胞的心脏同种异体耐受性的小鼠模型中制造 获得一个细胞自主功能失调状态，以防止其分化为分泌抗体细胞 这对T细胞的帮助有能力。但是，这些耐受性细胞并不完全惰性，显着的是 我们建议定义：目标1。体内细胞 供体反应性B细胞具有内在耐受性的要求；目标2。维持供体的机制 - 特定的B细胞中性耐受性并防止其发育成抗体分泌细胞；目标3。 耐受性B细胞介导的抑制的机制和后果。我们预计完成 这些研究将提供有关导致和维持B细胞耐受性的新机制的见解， 将耐受性B细胞与幼稚或效应子/记忆B细胞和潜在治疗区分开的生物标志物 控制移植受体中同种异体特异性抗体反应的靶标。