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: 9361832
• 负责人: Effie W Petersdorf
• 金额: $ 66万
• 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/9361832
• 关键词: Acute; Adverse effects; African; Alleles; American; Asians; 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; 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; hematopoietic cell transplantation; high risk; identity by descent; immunogenicity; improved; leukemia; mortality; permissiveness; 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匹配和不匹配的相关且无关的供体造血细胞移植 可以治愈威胁生命的血液疾病。患者的未满足需求是确定最佳 移植供体，以及降低急性和慢性移植抗宿主病（GVHD）的风险， 复发和死亡率。我们最近发现HLA-C和HLA-的表达水平 DP同型定义（非）允许不匹配。患者不匹配高表达 与低表达相比，异型与GVHD和死亡率的高风险有关 同种型，应尽可能避免。在HLA-A，B，C，DR，DQ中，DP匹配的无关 供体移植，高表达HLA-DP同型的潜力与高有关 GVHD的风险与无高表达同种型相比。这些数据首先证明了 HLA蛋白的量与HLA蛋白的种类一样重要。我们有说服力的数据 HLA-DR和DQ表达是特异性的。我们建议HLA匹配，并 通过了解HLA-DR 和DQ表达。具体目的是：确定HLA-DR和DQ同型和 单倍型特异性表达；定义5'，编码，3'和XL9区域变体，以用于不同的dr- DQ等位基因；将调节序列变化与表达相关，并定义临床 DR/DQ表达在匹配和不匹配的移植中的重要性。这个建议 将填补由表达式定义的HLA屏障中的知识差距。信息将 提高需要这种生命的患者的安全性，效率和可用性 - 保存疗法。