Deconstructing the allo-specific memory B cell response

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物排斥，特别是在具有预先存在的供体特异性抗体（DSA）的“致敏”移植受者中。致敏受者的抗体来源于两个不同的细胞库：来自长寿浆细胞的同种特异性抗体的组成性产生和来自回忆反应中重新激活的记忆B细胞的从头产生。虽然长寿命浆细胞可被视为产生有限量抗体（寿命乘以分泌速率）的静态群体，但记忆B细胞代表高度动态的群体，其无限地再循环以产生抗体爆发并重新接种长寿命浆细胞和记忆B细胞库。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，最终将被证明是重要的控制移植排斥反应。我们的工作揭示了B细胞分化的中心调节因子，其控制分化的B细胞的身份，作为B细胞抗原受体（BCR）的抗原亲和力/亲合力的函数。Irf 4转录因子通过激活分别对浆细胞（PC）和Germinal Center B（GC B）细胞的命运重要的限速转录因子Blimp-1和Bcl 6的表达来控制这些细胞的产生。我们假设Irf 4在控制记忆B细胞的产生以及控制记忆B细胞再激活的动力学中起着类似的关键作用。此外，我们优化了一种策略，以跟踪单个同种异体MHC特异性B细胞对移植反应的命运 对小鼠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，以确定记忆B细胞重新激活的条件，并确定记忆B细胞对体液排斥机制的影响。

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.