Clinical Significance of MHC Haplotypes in HCT

描述（由申请方提供）：CA100019的长期目标是通过更好地了解移植屏障的免疫遗传学，改善非亲缘供者（URD）造血细胞移植（HCT）的结局，并拓宽不匹配HCT的应用。我们假设基因密集型MHC中未检测到的变异可能会导致HLA匹配和HLA不匹配的URD HCT后的风险。我们开发了一种新的远程定相方法来连接无关个体中的HLA等位基因，并证明在HLA匹配和HLA不匹配的HCT后，单倍型不匹配与临床严重急性移植物抗宿主病（GVHD）的高风险相关。HLA等位基因和单倍型均不匹配的患者生存率显著降低。单倍型不匹配的供体和受体与单倍型匹配的供体和受体相比，MHC居民变异的差异程度更大，未检测到的差异与移植后风险增加相关。这些数据表明，单倍型是移植风险的代理。为了在更大的独立临床移植人群中确定GVHD、复发、TRM和死亡率的风险，我们将改进我们的远程定相方法，并开发短程定相方法来绘制变异（具体目标1）。我们将确定单倍型匹配在多大程度上可以降低GVHD和TRM的风险，同时保持移植物抗白血病效应（具体目标2）。我们将确定与移植风险相关的新的MHC驻留变异（具体目标3）。CA100019将为优化URD HCT和扩大HLA不匹配URD的使用提供一种强有力的实用免疫遗传学方法。最后，CA100019将为假设驱动和探索性基因定位提供所需的新遗传数据。 公共卫生相关性：我们开发了一种研究人类染色体和基因的工具，并发现了改善非亲缘移植治疗血液疾病结果的方法。我们将使用该工具来找到对移植成功至关重要的基因。

DESCRIPTION (provided by applicant): The long-term goals of CA100019 are to improve the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT) and broaden the application of mismatched HCT through a better understanding of the immunogenetics of the transplantation barrier. We hypothesize that undetected variation within the gene- dense MHC could contribute to risks after HLA-matched and HLA-mismatched URD HCT. We developed a novel long-range phasing method to link HLA alleles in unrelated individuals and demonstrated that haplotype mismatching is associated with higher risk of clinically severe acute graft-versus-host disease (GVHD) after HLA matched and HLA mismatched HCT. Patients mismatched for both HLA alleles and haplotypes had significantly lower survival. Haplotype-mismatched donors and recipients had a greater degree of disparity for MHC-resident variation compared to haplotype-matched pairs, and undetected disparity was associated with increased post-transplant risks. These data demonstrate that the haplotype is a proxy for transplant risk. To define the risks of GVHD, relapse, TRM and mortality in a larger independent clinical transplant population, we will refine our long-range phasing method and develop short-range phasing methods to map variation (Specific Aim 1). We will determine the extent to which haplotype matching can lower risks of GVHD and TRM, while preserving graft-versus-leukemia effects (Specific Aim 2). We will identify novel MHC-resident variation associated with transplant risks (Specific Aim 3). CA100019 will provide a powerful practical immunogenetic approach for optimizing URD HCT and for broadening the use of HLA mismatched URDs. Finally, CA100019 will contribute novel genetic data needed for hypothesis-driven and exploratory gene mapping. PUBLIC HEALTH RELEVANCE: We developed a tool for studying human chromosomes and genes, and discovered ways to improve the results of unrelated transplantation for the treatment of blood disorders. We will use the tool to find the genes that are important to transplant success.