Immuno and Epigenetics of Hematopoietic Cell Transplantation

项目摘要/摘要 来自亲缘关系和非亲缘关系捐赠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(GVHD)和复发仍然是主要障碍。当匹配的捐赠者 都是不可用的，管理(不)有利的HLA错配的属性没有很好地定义。这些 对于大部分缺乏匹配的捐献者的患者来说，缺陷具有重要的意义。 所有有疾病复发风险的患者。改进的GVHD预防方案的出现增加了 单倍体相合移植的安全性和有效性及其在多位点失配中的应用 不相关的移植将大大增加患者的选择。未得到满足的需求需要理解 人类白细胞抗原-DR和-DQ基因调节移植风险的机制，以及应用 将研究成果转化为临床护理。我们最近发现了人类白细胞抗原-DQ分子的重要特征和 描述(不)有利错配的HL-DR表达，它们代表了一种全新的 人类白细胞抗原II类区域。我们建议定义匹配和匹配的基本机制 移植中的HLA-DR和-DQ功能不匹配。具体目的是：确定人类白细胞抗原的作用- DQ结构和表达在预后中的作用；确定HLADRβ分子在预后中的作用；确定 人类白细胞抗原-DR-DQ单倍型变异对人类白细胞抗原相合和不相合异基因移植后临床结局的影响 移植，以及将II类特征转化为临床实践的设计工具。这些目标将会实现。 通过系统分析人类白细胞抗原-DR和-DQ的变异、多肽谱系和在大民族中的表达 具有完整临床数据的不同移植人群。这项建议将填补中国的知识空白 移植物抗宿主病与移植后复发和存活的免疫生物学基础这一信息将增加 对于所有需要这种救命疗法的患者，移植的安全性、有效性和可用性。

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.