Section of Transplantation Immunology, Department of Stem Cell Transplant and Cellular Therapy, M.D. Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2011;6(8):e23217. doi: 10.1371/journal.pone.0023217. Epub 2011 Aug 9.
Minor histocompatibility antigens (mHA) mediate much of the graft vs. leukemia (GvL) effect and graft vs. host disease (GvHD) in patients who undergo allogeneic stem cell transplantation (SCT). Therapeutic decision making and treatments based upon mHAs will require the evaluation of multiple candidate mHAs and the selection of those with the potential to have the greatest impact on clinical outcomes. We hypothesized that common, immunodominant mHAs, which are presented by HLA-A, B, and C molecules, can mediate clinically significant GvL and/or GvHD, and that these mHAs can be identified through association of genomic data with clinical outcomes.
METHODOLOGY/PRINCIPAL FINDINGS: Because most mHAs result from donor/recipient cSNP disparities, we genotyped 57 myeloid leukemia patients and their donors at 13,917 cSNPs. We correlated the frequency of genetically predicted mHA disparities with clinical evidence of an immune response and then computationally screened all peptides mapping to the highly associated cSNPs for their ability to bind to HLA molecules. As proof-of-concept, we analyzed one predicted antigen, T4A, whose mHA mismatch trended towards improved overall and disease free survival in our cohort. T4A mHA mismatches occurred at the maximum theoretical frequency for any given SCT. T4A-specific CD8+ T lymphocytes (CTLs) were detected in 3 of 4 evaluable post-transplant patients predicted to have a T4A mismatch.
CONCLUSIONS/SIGNIFICANCE: Our method is the first to combine clinical outcomes data with genomics and bioinformatics methods to predict and confirm a mHA. Refinement of this method should enable the discovery of clinically relevant mHAs in the majority of transplant patients and possibly lead to novel immunotherapeutics.
次要组织相容性抗原（mHA）在接受异基因干细胞移植（SCT）的患者中介导移植物抗白血病（GvL）效应和移植物抗宿主病（GvHD）的大部分作用。基于 mHA 的治疗决策和治疗将需要评估多个候选 mHA，并选择那些对临床结果有最大影响的 mHA。我们假设常见的免疫显性 mHA，由 HLA-A、B 和 C 分子呈递，可以介导具有临床意义的 GvL 和/或 GvHD，并且可以通过将基因组数据与临床结果相关联来识别这些 mHA。
方法/主要发现：由于大多数 mHA 是由供体/受者 cSNP 差异引起的，我们对 57 例髓系白血病患者及其供体进行了 13917 个 cSNP 的基因分型。我们将遗传预测的 mHA 差异频率与免疫反应的临床证据相关联，然后通过计算筛选所有映射到高度相关 cSNP 的肽，以评估它们与 HLA 分子结合的能力。作为概念验证，我们分析了一个预测的抗原 T4A，其 mHA 错配在我们的队列中呈改善总生存和无病生存的趋势。T4A mHA 错配发生在任何给定 SCT 的最大理论频率。在预测有 T4A 错配的 4 名可评估移植后患者中的 3 名中检测到 T4A 特异性 CD8+CTLs。
结论/意义：我们的方法是首次将临床结果数据与基因组学和生物信息学方法相结合，以预测和证实 mHA。这种方法的改进应该能够在大多数移植患者中发现具有临床意义的 mHA，并可能导致新的免疫疗法。
