Deconstructing the allo-specific memory B cell response

解构同种异体特异性记忆 B 细胞反应

• 批准号: 8671244
• 负责人: Roger Sciammas
• 金额: $ 41.17万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671244
• 关键词: Accounting; Acute; Address; Affinity; Alloantigen; Allogenic; Antibodies; Antibody Affinity; Antibody Formation; Antigens; Avidity; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Behavior; Cell Differentiation process; Cells; Chronic; Clinical; Clinical Management; Cues; Data; Exposure to; Favorable Clinical Outcome; Future; Generations; Genetic; Graft Rejection; HLA Antigens; Imagery; Immune response; Immunization; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Infection; Isoantibodies; Kinetics; Laboratories; Life; Life Cycle Stages; Longevity; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mus; Organ Transplantation; Outcome; Patients; Plasma Cells; Play; Population; Population Dynamics; Production; Reaction; Receptors, Antigen, B-Cell; Recycling; Regulation; Role; Secondary Immunization; Solid; Source; Structure of germinal center of lymph node; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Work; allograft rejection; base; cell type; differentiated B cell; insight; mouse model; novel; novel therapeutics; plasma cell differentiation; public health relevance; response; tool; transcription factor

DESCRIPTION (provided by applicant): Deconstructing the allo-specific memory B cell response Allo-specific B cells and their antibody products are strongly predict with acute and chronic allograft rejection, especially in "sensitized" transplant recipients with pre-existing donr-specific antibodies (DSA). The source of antibody in the sensitized recipients derives from two distinct cellular pools: constitutive production of allo-specific antibody from the long lived plasa cell and de novo production from reactivated memory B cells in the recall response. While the long lived plasma cells can be viewed as a static population that produces a finite amount of antibody (life time times secretion rate), memory B cells represent a highly dynamic population that re- cycle indefinitely to produce bursts of antibody and to reseed the long lived plasma cell and memory B cell pools. Thus, we posit that understanding the roles of memory B cells under circumstances of transplantation, especially the mechanisms that regulate the dynamic behavior of allo-specific memory B cells, will ultimately prove to be important for controlling transplant rejection. Our work has uncovered a central regulator of B cell differentiation that controls the identity of differentiated B cells as a function of antigen affinity/avidity of the B cell antigen receptor (BCR). The Irf4 transcription factor controls the generation of plasma cells (PC) and Germinal Center B (GC B) cells by activating the expression of the rate limiting transcription factors important for those cell fates, Blimp-1 and Bcl6, respectively. We hypothesize that Irf4 plays a similarly critical role in controlling the generation of memory B cells as well as in controlling the dynamics of memory B cell reactivation. Furthermore, we have optimized a strategy to follow the fate of individual allogeneic MHC-specific B cells responding to transplants in mice. This technology has enabled us to quantify the proportions of PC, GC B, and memory B cells after primary and secondary immunizations. Therefore we propose to define the life cycle of allo-antigen specific memory B cells and how that may be altered by costimulation blockade, to identify the conditions with which memory B cells reactivate, and to determine the impact of memory B cells on mechanisms of humoral rejection.

描述（由申请人提供）：解构同种异体特异性记忆 B 细胞反应同种异体特异性 B 细胞及其抗体产物强烈预测急性和慢性同种异体移植排斥反应，特别是在具有预先存在的供体特异性抗体的“致敏”移植受者中（DSA）。致敏受体中的抗体来源来自两个不同的细胞池：由长寿的浆细胞组成型产生同种异体特异性抗体，以及在回忆反应中由重新激活的记忆B细胞从头产生。虽然长寿命浆细胞可以被视为产生有限量抗体（寿命乘以分泌率）的静态群体，但记忆 B 细胞代表高度动态的群体，它们无限期地循环以产生抗体爆发并重新播种抗体。长寿的浆细胞和记忆 B 细胞池。因此，我们认为了解记忆 B 细胞在移植情况下的作用，特别是调节同种异体特异性记忆 B 细胞动态行为的机制，最终将被证明对于控制移植排斥非常重要。我们的工作发现了 B 细胞分化的中央调节因子，它根据 B 细胞抗原受体 (BCR) 的抗原亲和力/亲合力来控制分化 B 细胞的身份。 Irf4 转录因子通过激活对细胞命运至关重要的限速转录因子 Blimp-1 和 Bcl6 的表达来控制浆细胞 (PC) 和生发中心 B (GC B) 细胞的生成。我们假设 Irf4 在控制记忆 B 细胞的生成以及控制记忆 B 细胞重新激活的动态方面发挥着类似的关键作用。此外，我们还优化了一种策略来跟踪单个同种异体 MHC 特异性 B 细胞对移植作出反应的命运 在小鼠中。这项技术使我们能够量化初次和二次免疫后 PC、GC B 和记忆 B 细胞的比例。因此，我们建议定义同种异体抗原特异性记忆 B 细胞的生命周期，以及如何通过共刺激阻断来改变生命周期，以确定记忆 B 细胞重新激活的条件，并确定记忆 B 细胞对体液机制的影响。拒绝。