Cellular and Molecular Determinants of RBC Alloimmunization Responder Status

项目摘要 红细胞同种异体免疫是慢性输血治疗的主要并发症。对于那些患者来说 不幸的是他们产生了多种同种异体抗体，提供了相容的抗原阴性 RBC可能既耗费时间又耗费资源。在极少数情况下，这可能会导致无法定位 否则就是救命疗法。在长期输血的患者中，患有镰刀细胞病(SCD)的患者 不成比例地遭受同种免疫。这项提案旨在确定蜂窝和 SCD患者应答者与非应答者状态的分子控制器。我们最重要的假设是 细胞因子对T滤泡辅助细胞(TFH)亚群分化的差异控制 SCD患者中应答者与非应答者状态的一般同种免疫应答 很特别。这一建议结合了对实验上易处理的特定细胞因子小鼠模型的研究 细胞因子诱导的人外周血淋巴细胞TFH分化试验 健康供者和SCD患者。通过提供一种能够解释和预测 SCD患者的应答者状况，这项建议可能会对输血护理产生重大影响 在SCD患者中。在开始输血治疗之前了解患者的应答者状态将允许 更个性化和量身定制的治疗方法。例如，我们可以确定哪些患者是 可能从扩展的表型匹配方案中获得最大的好处。最终，理解 规定响应者状态的分子调节器也将有助于识别潜在的目标 未来的治疗干预。

Project Summary RBC alloimmunization represents a major complication of chronic transfusion therapy. For those patients 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. Among chronically transfused patients, those with Sickle Cell Disease (SCD) suffer disproportionately from alloimmunization. This proposal sets out to determine the cellular and molecular controllers of responder vs. non-responder status in SCD patients. Our overarching hypothesis is that differential control of T follicular helper cell (TFH) subset differentiation by cytokines is responsible for alloimmunization responses in general, and for responder vs. non-responder status in SCD patients in particular. This proposal combines studies of experimentally tractable mouse models of specific cytokine deficiency with cytokine driven TFH differentiation assay performed on human lymphocytes from both healthy donors and SCD patients. By providing a molecular mechanism capable of explaining and predicting responder status among SCD patients, this proposal could have a significant impact on the transfusion care of SCD patients. Knowing a patient's responder status prior to initiating transfusion therapy would allow for a more personalized and tailored therapeutic approach. For example, we could determine which patients are likely to get the most benefit from extended phenotype matching protocols. Ultimately, understanding the molecular regulators that dictate responder status would also help in the identification of potential targets for future therapeutic intervention.