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/文摘