Immuno and Epigenetics of Hematopoietic Cell Transplantation

血缘和非血缘供者的HLA相合和不相合造血细胞移植 可以治愈危及生命的血液疾病。患者未得到满足的需求是确定最佳的 为了降低急性和慢性移植物抗宿主病(GVHD)的风险， 复发和死亡率。我们新近发现，人类白细胞抗原-C和人类白细胞抗原-1的表达水平。 DP同种类型定义(非)允许的不匹配。患者因高表达而错配 与低表达相比，同种异型与GVHD和死亡率的高风险相关 在可能的情况下，应避免使用。在人类白细胞抗原-A、B、C、DR、DQ、DP相合无关 供者移植，拥有高表达的HLA-DP同种异型与高 与没有高表达的同种异型相比，GVHD的风险。这些数据有力地证明了 人类白细胞抗原蛋白的数量与人类白细胞抗原的种类同样重要。我们有令人信服的数据 HL A-DR和DQ的表达具有同种异型特异性。我们认为人类白细胞抗原相合的和 了解人类白细胞抗原-DR可以改善不相合的亲缘和非亲缘移植 和DQ表达。具体目的是：确定人类白细胞抗原-DR和DQ同种异型和 单倍型特异性表达；定义不同DR的5‘、编码、3’和XL9区域变体 DQ等位基因；将调节序列变异与表达联系起来，并定义临床 DR/DQ表达在相合和不相合移植中的意义这项建议 将填补表达所定义的人类白细胞抗原屏障的知识空白。这些信息将会 为需要此生的患者增加移植的安全性、有效性和可用性- 拯救疗法。

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.