Cellular and Molecular Determinants of RBC Alloimmunization Responder Status

红细胞同种免疫应答状态的细胞和分子决定因素

• 批准号: 10192795
• 负责人: CHANCE MARION JOHN LUCKEY
• 金额: $ 42.41万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192795
• 关键词: Alloimmunization; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Caring; Cell Differentiation process; Cell Maturation; Cells; Cessation of life; Chronic; Clinical; Complication; Cytokine Network Pathway; Cytokine Signaling; Data; Diagnostic; Disease; Erythrocytes; Future; Generations; Helper-Inducer T-Lymphocyte; Human; Immunobiology; Immunoglobulin Class Switching; Immunoglobulin G; Individual; Interleukin-6; Isoantibodies; Life; Lymphocyte; Mediating; Modeling; Molecular; Mus; National Heart, Lung, and Blood Institute; Patients; Phenotype; Plasma Cells; Play; Population; Process; Production; Protocols documentation; Publishing; Reporter; Resources; Risk; Role; Savings; Science; Sickle Cell Anemia; Signal Pathway; State Medicine; Testing; Therapeutic; Therapeutic Intervention; Time; Transfusion; clinical development; clinically relevant; cytokine; experimental study; functional outcomes; high risk; in vivo; mouse model; novel; patient population; responders and non-responders; response; symposium; transfusion medicine

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.

项目摘要 RBC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 不幸产生多种同种抗体的患者，提供相容性抗原阴性 RBC可能是时间和资源密集型的。在极少数情况下，这可能会导致无法找到 否则就是救命的治疗在长期输血患者中，镰状细胞病（SCD） 不成比例地遭受同种免疫。该提案旨在确定蜂窝和 SCD患者中应答者与非应答者状态的分子控制器。我们的首要假设是 细胞因子对T滤泡辅助细胞（TFH）亚群分化的差异控制是导致 一般同种免疫反应，以及SCD患者中反应者与非反应者状态 特别的。该建议结合了对特定细胞因子的实验易处理小鼠模型的研究， 对来自两种来源的人淋巴细胞进行细胞因子驱动的TFH分化测定 健康供体和SCD患者。通过提供能够解释和预测的分子机制 SCD患者中的应答者状态，这一建议可能对输血护理产生重大影响 SCD患者。在开始输血治疗之前了解患者的应答者状态将允许 更个性化和定制的治疗方法。例如，我们可以确定哪些患者 可能从扩展的表型匹配方案中获得最大的益处。最终，了解 决定应答者状态的分子调节剂也将有助于识别潜在的靶点， 未来的治疗干预。