Immunogenetics of Outcomes Disparities after Allogeneic HCT

同种异体 HCT 后结果差异的免疫遗传学

• 批准号: 10601325
• 负责人: Effie W Petersdorf
• 金额: $ 9.32万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601325
• 关键词: Immunogenetics; Outcomes; Disparities; after; Allogeneic

Abstract We have identified genetic variants within the IL6 and NKG2 pathways that influence outcomes disparities after unrelated donor hematopoietic cell transplantation (HCT). Patient and donor variants for the IL6ST subunit are associated with increased risk of GVHD and mortality particularly in patients of African and Hispanic ancestry, compared to patients of Asian and Caucasian ancestry. Information on both IL6ST as well as IL6R demonstrate that risks are imparted by ancestry-specific coding and regulatory variants that affect the type and quantity of proteins produced. The second genetic system, NKG2, also plays a critical role in allorecognition in HCT. Recipient HLA-E and MICA ligands together with donor NKG2A, NKG2C, NKG2D receptors are highly polymorphic and differ by ancestry. Together, both models showcase the importance of understanding the ligand and its receptor, to fully clarify their clinical importance. Information on the contribution of IL6 and NKG2 systems to clinical outcome will elucidate the risks traditionally associated with donor-recipient HLA matching. We will test novel hypotheses in three aims: 1) define the impact of IL6ST and IL6R variation on expression and HCT outcome; 2) define NKG2 ligand-receptor features that influence HCT outcomes, and 3) estimate the risks associated with HLA mismatching in HCT. Information on haplotype content and expression in ethnically- diverse transplant populations will significantly advance understanding of outcomes disparities in US transplants.

抽象的 我们已经确定了IL6和NKG2途径中影响结果差异的遗传变异 无关的供体造血细胞移植（HCT）。 IL6st亚基的患者和供体变体是 与GVHD和死亡率的增加有关，特别是在非洲和西班牙裔血统的患者中， 与亚洲和高加索血统的患者相比。有关IL6ST和IL6R的信息 证明风险是通过影响类型和类型和的监管变体所赋予的 产生的蛋白质数量。第二个遗传系统NKG2在同种认识中也起着至关重要的作用 HCT。接受者HLA-E和云母配体以及供体NKG2A，NKG2C，NKG2D受体高度高 多态性，祖先不同。这两个模型一起展示了理解的重要性 配体及其受体，以充分阐明它们的临床重要性。有关IL6和NKG2的贡献的信息 进行临床结果的系统将阐明传统上与供​​体 - 接收者HLA匹配相关的风险。 我们将以三个目的测试新的假设：1）定义IL6ST和IL6R变化对表达的影响 和HCT结果； 2）定义影响HCT结果的NKG2配体受体特征，3）估计 HCT中HLA不匹配的风险。关于单倍型含量和表达的信息 多样化的移植人群将大大提高人们对美国结果差异的理解 移植。