RH genotype matched red cell transfusions for patients with sickle cell disease

镰状细胞病患者 RH 基因型匹配的红细胞输注

• 批准号: 10259737
• 负责人: STELLA T CHOU
• 金额: $ 83.48万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259737
• 关键词: Address; Adverse effects; African; African American; Alleles; Alloimmunization; Antibodies; Antibody Formation; Antigens; Biological Assay; Blood; Blood Banks; Blood donor; Blood group antibody D; Caring; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Complex; Complication; Custom; D Cells; DNA; Donor Selection; Effectiveness; Equipment and supply inventories; Erythrocyte Transfusion; Erythrocytes; Event; Exposure to; Frequencies; Gene Duplication; Gene Family; Gene Frequency; Genes; Genetic; Genetic Heterogeneity; Genetic Recombination; Genetic Variation; Genotype; Goals; Hemolysis; Hospitals; Hybrids; Incidence; Individual; Institution; Knowledge; Lead; Life; Methods; Minority; Modeling; Monitor; Morbidity - disease rate; Multicenter Studies; Patient Care; Patient Monitoring; Patients; Phase; Phenotype; Prospective Studies; Proteins; Recording of previous events; Research Personnel; Rh-Hr Blood-Group System; Risk Factors; Safety; Savings; Serology; Services; Sickle Cell Anemia; System; Technology; Transfusion; Variant; Visit; base; bench to bedside; clinical practice; clinically significant; cohort; cost; cost effective; data management; design; effectiveness evaluation; feasibility testing; genetic variant; improved; innovation; new technology; next generation sequencing; novel; novel sequencing technology; precision medicine; prevent; prophylactic; prospective; recruit

ABSTRACT Red blood cell transfusion remains a life-saving therapy for patients with sickle cell disease (SCD). A major problem is the high rate of alloimmunization (antibody formation against transfused red cells) that occurs in transfused patients with SCD. Alloimmunization leads to delays in care, increases costs, and makes transfusion therapy unsafe and impossible for some patients. The most common antibodies formed by patients with SCD are directed against the Rh blood group system. Genetic diversity in Rh antigens in patients and blood donors of African descent contributes to this high incidence and complexity of antibodies found in patients with SCD. Recent studies performed by our group and others demonstrate RH genetic variants in patients and donors is a major risk factor leading to Rh alloimmunization. Routine blood bank assays can not identify these variants, so although Rh-matched red cells are transfused to patients with SCD, they would only be truly Rh-matched with DNA-based matching. Genetic matching of donor units at the RH loci may prevent Rh alloimmunization but no clinical trials have been conducted. Major barriers are the current cost of RH genotyping as well as inventory and data management of donor genotypes to identify RH matched units for patients. The major goal of this proposal is to perform pilot clinical studies to provide RH genotype matched red cells to chronically transfused patients with SCD. We will determine the feasibility of identifying adequate genotype matched donor units in real clinical practice, identify barriers, and prospectively monitor patients for Rh alloimmunization. A second goal for this proposal is to apply new technologies to improve our knowledge of the two RH genes, RHD and RHCE, which due to their high sequence similarity, currently makes it challenging to apply low cost sequencing methods to provide RH genotype matched red cells for all patients with SCD. In this application, we propose three integrated aims that can address the current challenges of transfusion therapy for SCD, and will drive the field forward by providing innovative solutions to these current obstacles.

摘要 对于镰状细胞病(SCD)患者来说，红细胞输注仍然是一种挽救生命的疗法。一位少校 问题是同种异体免疫的高比率(针对输血红细胞的抗体形成)发生在 输血的SCD患者。同种异体免疫导致延迟护理，增加费用，并使输血 对一些患者来说，治疗是不安全的，也是不可能的。SCD患者形成的最常见抗体 是针对Rh血型系统的。患者和献血员Rh抗原的遗传多样性 在SCD患者中发现的抗体的高发生率和复杂性是非洲裔的原因之一。 我们小组和其他人最近进行的研究表明，患者和捐赠者中的RH基因变异是一种 导致Rh异体免疫的主要危险因素。常规的血库检测不能识别这些变异，所以 尽管Rh相合的红细胞被输注给SCD患者，但它们只有在真正的Rh相合的情况下才会被 基于DNA的匹配。Rh基因座上供体单位的基因匹配可能会阻止Rh同种免疫，但不会 已经进行了临床试验。主要障碍是RH基因分型的当前成本以及库存 以及供体基因型别的数据管理，以确定患者的RH匹配单位。这一行动的主要目标是 建议进行试验性临床研究，为长期输血提供RH基因型匹配的红细胞 SCD患者。我们将确定在现实中确定足够的基因匹配的供体单位的可行性。 临床实践，识别障碍，并前瞻性监测患者的Rh同种异体免疫。第二个目标是 这项建议是应用新技术来提高我们对RHD和RHCE两个RH基因的了解， 由于它们的序列相似性很高，这使得目前应用低成本的测序方法具有挑战性 为所有SCD患者提供RH血型匹配的红细胞。在本申请中，我们提出了三个 综合目标，可以应对当前SCD输血治疗的挑战，并将推动该领域 通过为这些当前的障碍提供创新的解决方案来向前迈进。