Immuno and Epigenetics of Hematopoietic Cell Transplantation

造血细胞移植的免疫和表观遗传学

• 批准号: 10660131
• 负责人: Effie W Petersdorf
• 金额: $ 62.31万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660131
• 关键词: Acute Graft Versus Host Disease; Affect; African; Alleles; Allogenic; Asian; Autoimmunity; Binding; Biology; Caucasians; Clinical; Clinical Data; Cyclophosphamide; Data; Disease-Free Survival; Disparity; Donor Selection; Dose; Epigenetic Process; Epitopes; Ethnic Origin; Exons; Failure; Future; Genes; Goals; HLA-B Antigens; HLA-C Antigens; HLA-DQ Antigens; HLA-DR Antigens; HLA-DRB1; Haplotypes; Hematological Disease; Hispanic; Histocompatibility; Homologous Transplantation; Investigation; Knowledge; Laboratories; Life; Link; Methods; Modeling; Nature; Outcome; Patients; Peptides; Phenotype; Population; Procedures; Property; Publishing; Race; Recurrent disease; Regimen; Relapse; Research; Risk; Risk Factors; Role; Safety; Selection Criteria; Siblings; Structure; Tissues; Translating; Transplant Recipients; Transplantation; Untranslated RNA; Variant; Work; clinical care; clinical decision-making; clinical practice; clinically relevant; design; disorder prevention; disorder risk; ethnic diversity; graft vs host disease; hematopoietic cell transplantation; high risk; immunogenicity; improved; individualized medicine; innovation; mortality; mortality risk; novel; post-transplant; preference; relapse risk; stem; success; survivorship; tool

PROJECT SUMMARY/ABSTRACT Hematopoietic cell transplantation from related and unrelated donors can cure life-threatening blood disorders; however, graft-versus-host disease (GVHD) and relapse remain the major obstacles. When matched donors are not available, the properties of that govern (un)favorable HLA mismatches are not well-defined. These deficiencies have important implications for a large fraction of patients who lack HLA-matched donors, and for all patients at risk for disease relapse. The advent of improved GVHD prevention regimens has increased the safety and efficacy of haploidentical transplantation and it is anticipated that its use in multi-locus mismatched unrelated transplantation will substantially increase options for patients. The unmet needs are to understand the mechanisms through which HLA-DR and -DQ genes modulate transplant risks, and a means to apply the research findings to clinical care. We have recently identified important features of HLA-DQ molecules and HLA-DR expression that describe (un)favorable mismatches, and they represent an entirely new paradigm for the HLA class II region. We propose to define the underlying mechanisms through which matched and mismatched HLA-DR and -DQ function in transplantation. The specific aims are to: determine the role of HLA- DQ structure and expression in outcome; determine the role of HLA-DRβ molecules in outcome; determine the impact of HLA-DR-DQ haplotype variation on clinical outcome after HLA-matched and -mismatched allogeneic transplantation, and design tools to translate class II features into clinical practice. The goals will be achieved through systemic analysis of HLA-DR and -DQ variation, peptide repertoire and expression in large ethnically diverse transplant populations with complete clinical data. This proposal will fill the knowledge gap in the immunobiological basis of GVHD, relapse and survivorship in transplantation. The information will increase the safety, efficacy and availability of transplantation for all patients in need of this life-saving therapy.

项目总结/摘要 来自亲缘和非亲缘供者的造血细胞移植可以治愈危及生命的血液疾病; 然而，移植物抗宿主病和复发仍然是主要障碍。当匹配的捐赠者 没有可用的，支配（不）有利的HLA错配的属性没有很好地定义。这些 缺乏对大部分缺乏HLA匹配供体的患者具有重要意义， 所有患者都有疾病复发的风险。改进的GVHD预防方案的出现增加了 单倍相合移植的安全性和有效性，并预计其在多位点不匹配的 无关移植将大大增加患者的选择。未满足的需求是了解 HLA-DR和-DQ基因调节移植风险的机制，以及应用 研究结果应用于临床护理。我们最近发现了HLA-DQ分子的重要特征， HLA-DR表达描述了（不）有利的错配，它们代表了一个全新的范式， HLA II类区域我们建议定义匹配的基本机制， 移植中HLA-DR和-DQ功能不匹配。具体目标是：确定HLA的作用- DQ结构和表达在结果中的作用;确定HLA-DR β分子在结果中的作用;确定 HLA-DR-DQ单倍型变异对HLA相合和不相合同种异体移植后临床结局影响 移植，并设计工具，将II类功能转化为临床实践。目标一定会实现 通过系统分析HLA-DR和-DQ的变异、肽库和在大的种族中的表达， 具有完整临床数据的不同移植人群。这一建议将填补知识空白， 移植物抗宿主病免疫生物学基础、移植复发和存活这些信息将增加 安全性，有效性和移植的所有患者需要这种挽救生命的治疗的可用性。