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: 9980803
• 负责人: Effie W Petersdorf
• 金额: $ 59.85万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980803
• 关键词: Acute; African American; Alleles; American; Asian Americans; Blood; Bone Marrow Transplantation; Caucasians; Characteristics; Chronic; Clinical; Code; Cyclophosphamide; Data; Donor Selection; Donor person; Effectiveness; Engraftment; Epigenetic Process; Failure; Genotype; HLA-A gene; HLA-C Antigens; HLA-DP Antigens; HLA-DR Antigens; Haplotypes; Hematological Disease; Hispanic Americans; Homologous Transplantation; Immunosuppression; Isogenic transplantation; Knowledge; Life; Modality; Modeling; Morbidity - disease rate; Nucleic Acid Regulatory Sequences; Outcome; Patients; Proteins; Regimen; Relapse; Relaxation; Risk; Safety; Savings; Selection Criteria; Siblings; Source; Structure; Tissues; Transplant Recipients; Transplantation; Untranslated RNA; Variant; chronic graft versus host disease; clinically relevant; clinically significant; design; disorder risk; graft failure; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; high risk; identity by descent; immunogenicity; improved; mortality; post-transplant; side effect; tool

HLA-matched and mismatched related and unrelated donor hematopoietic cell transplantation can cure life-threatening blood disorders. The unmet needs of patients are to identify the optimal transplant donor, and to lower risks of acute and chronic graft-versus-host disease (GVHD), relapse and mortality. We recently discovered that the level of expression of HLA-C and HLA- DP allotypes defines (non)permissive mismatches. Patient mismatching for high-expression allotypes is associated with high risks of GVHD and mortality compared to low-expression allotypes and should be avoided where possible. In HLA-A,B,C,DR,DQ,DP-matched unrelated donor transplantation, possession of high-expression HLA-DP allotypes is associated with high risk of GVHD compared to no high-expression allotypes. These data firmly demonstrate that the amount of HLA protein is as important as the kind of HLA protein. We have convincing data that HLA-DR and DQ expression is allotype-specific. We propose that HLA-matched and mismatched related and unrelated transplantation can be improved with knowledge of HLA-DR and DQ expression. The specific aims are to: determine HLA-DR and DQ allotype and haplotype-specific expression; define the 5’, coding, 3’ and XL9 region variants for diverse DR- DQ alleles; relate regulatory sequence variation to expression, and define the clinical significance of DR/DQ expression in matched and mismatched transplantation. This proposal will fill the knowledge gap in the HLA barrier as defined by expression. The information will increase the safety, efficacy and availability of transplantation for patients in need of this life- saving therapy.

HLA相合和不相合的亲缘和非亲缘供者造血细胞移植 可以治愈危及生命的血液疾病患者未满足的需求是确定最佳的 移植供体，并降低急性和慢性移植物抗宿主病（GVHD）的风险， 复发率和死亡率。我们最近发现，HLA-C和HLA-C的表达水平与HLA-B的表达水平有关。 DP同种异型定义（非）允许性错配。高表达患者不匹配 与低表达相比，同种异型与GVHD和死亡率的高风险相关 同种异型，应尽可能避免。在HLA-A、B、C、DR、DQ、DP匹配的无关 在供体移植中，拥有高表达的HLA-DP同种异型与高表达的HLA-DP相关。 GVHD的风险相比，没有高表达同种异型。这些数据有力地表明， HLA蛋白的种类与HLA蛋白的量同样重要。我们有令人信服的数据， HLA-DR和DQ的表达具有同种异型特异性。我们建议，HLA匹配， HLA-DR的知识可以改善不匹配的相关和无关移植 DQ的表达。具体目的是：确定HLA-DR和DQ同种异型， 单倍型特异性表达;定义不同DR的5 '，编码，3'和XL 9区域变体。 DQ等位基因;将调控序列变异与表达相关，并定义临床 DR/DQ在配型与不配型移植中表达意义这项建议 将填补由表达定义的HLA屏障中的知识空白。这些信息将 提高安全性，有效性和可用性移植的病人需要这种生活- 拯救治疗