Cyokine control of red blood cell alloimmunization

总结。红细胞(RBC)同种异体免疫在输血中仍是一个重要的临床问题 药物，特别是那些需要长期输血的患者。对于那些不幸的人 足以产生多种同种异体抗体，可同时提供相容抗原阴性的红细胞 和资源密集型。在极少数情况下，这可能会导致无法找到原本可以挽救生命的疗法。 红细胞同种异体抗体也会引起溶血性输血反应(HTR)，导致大量 发病率和偶尔的死亡率。HTRs由两种重要的免疫现象引起。第一个是 RBC抗体的独特的消逝性质，其迅速消失导致假阴性 对接受过同种免疫的患者进行筛查。第二种是重新暴露于病毒引起的召回抗体反应 通过随后的输血，循环抗体的快速而强劲的增加推动HTR。 尽管这些现象带来了重大的临床后果，但我们对基本情况的理解 调节抗RBC抗体产生、维持和召回的分子和细胞机制是 非常有限。因此，没有有效的治疗干预措施可用于同种免疫 除抗原回避外的患者。我们之前的工作已经确定IL-6是一种关键的细胞因子信号， 调节红细胞和早期T滤泡辅助细胞(TFH)的初始同种免疫反应 差异化。我们现在有兴趣将我们的发现扩展到研究IL-6信号在脑内的作用 控制红细胞同种异体抗体消逝和召回反应。鉴于IL-6的多形性 信号，我们感兴趣的是确定细胞靶点(B细胞与T细胞)，下游信号 分子(STAT3)和细胞后果(短寿命浆细胞、长寿命浆细胞、记忆B细胞 和记忆TFH细胞分化)受IL-6调节，是红细胞同种异体免疫所必需的。因此， 我们将使用IL-6R、STAT3和BCL6的尖端条件遗传小鼠突变体来直接 比较两种不同的RBC同种免疫小鼠模型的抗体和细胞反应 标准的疫苗接种方法。通过这样做，我们将更好地理解基本的细胞和 RBC同种异体免疫的分子免疫调节因子因RBC抗原系统的不同而不同，以及如何 它们与传统的免疫刺激相比。此外，我们将开发一种临床前小鼠模型 系统确定靶向IL-6/IL-6R信号通路的治疗效果以预防 和/或红细胞同种异体免疫的治疗，作为随后审议IL-6R的关键数据 抗体阻断疗法(如Tocilizumab)用于选择的高危同种异体免疫患者。

Summary. Red blood cell (RBC) alloimmunization remains a significant clinical problem in transfusion medicine, particularly among those patients who require chronic transfusions. For those who are unfortunate enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can be both time and resource intensive. In rare cases, this can result in an inability to locate an otherwise life-saving therapy. RBC alloantibodies are also responsible for hemolytic transfusion reactions (HTRs), causing substantial morbidity and occasional mortality. HTRs result from two important immunological phenomena. The first is the uniquely evanescent nature of RBC antibodies, whose rapid disappearance leads to false negative screens in alloimmunized patients. The second is the recall antibody response elicited by re-exposure to antigen via subsequent transfusion, where the rapid and robust increase in circulating antibodies drive HTRs. Despite the significant clinical consequences of these phenomena, our understanding of the fundamental molecular and cellular mechanisms regulating anti-RBC antibody generation, maintenance and recall is remarkably limited. Accordingly, there are no effective therapeutic interventions available to alloimmunized patients other than antigen avoidance. Our previous work has identified IL-6 as a key cytokine signal that regulates both the initial alloimmunization response to RBCs as well as early T follicular helper cell (TFH) differentiation. We are now interested in extending our findings to investigate the role of IL-6 signals in controlling RBC alloantibody evanescence and recall responses. Given the pleomorphic nature of IL-6 signaling, we are interested in determining both the cellular targets (B vs. T cell), downstream signaling molecules (STAT3), and cellular consequences (short-lived plasma cell, long-lived plasma cell, memory B cell and memory TFH cell differentiation) regulated by IL-6 and required for RBC alloimmunization. Accordingly, we will employ cutting-edge conditional genetic mouse mutants of IL-6R, STAT3, and BCL6 to directly compare antibody and cellular responses to two different mouse models of RBC alloimmunization as well as standard vaccination approaches. In so doing, we will better understand how the fundamental cellular and molecular immune regulators of RBC alloimmunization vary for different RBC antigen systems, and also how they compare to traditional immune stimulation. Furthermore, we will develop a pre-clinical mouse model system to determine the therapeutic efficacy of targeting the IL-6/IL-6R signaling pathway for the prevention and/or treatment of RBC alloimmunization, serving as key data for the subsequent consideration of IL-6R antibody blocking therapies (such as Tocilizumab) in select, high-risk alloimmunized patients.