Systematic identification of minor histocompatibility antigens to address GVHD

系统鉴定次要组织相容性抗原以解决 GVHD

• 批准号: 10596181
• 负责人: Vincent Trien-Vinh Ho
• 金额: $ 73.85万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596181
• 关键词: Acute; Address; Affect; Algorithms; Alleles; Allogenic; Antigen Presentation; Antigen Targeting; Antigens; B-Lymphocytes; Binding; Biopsy; Biotechnology; Blood; Cell Line; Cells; Clinical; Code; Collaborations; Collection; Colon; Coupled; Cyclophosphamide; DNA; Data; Detection; Disparate; Donor Selection; Epitopes; Ethnic Origin; Evaluation; Event; Failure; Female; Genetic Variation; Genomics; Hematological Disease; Hematopoietic Stem Cell Transplantation; Immune response; Immunocompetent; Immunologics; Immunosuppression; Individual; Inflammation; Inherited; Institution; Life; Link; Liver; Lung; Maps; Minor Histocompatibility Antigens; Modeling; Molecular; Morbidity - disease rate; Myelogenous; Neoplasms; Organ; Outcome; Patients; Peptides; Peripheral Blood Mononuclear Cell; Principal Investigator; Prophylactic treatment; Proteins; Proteomics; Reporting; Risk Assessment; Single Nucleotide Polymorphism; Skin; Somatic Mutation; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Transplantation; Validation; Writing; Y Chromosome; analysis pipeline; antigen-specific T cells; candidate identification; chronic graft versus host disease; clinically relevant; design; disorder risk; exome; exome sequencing; experience; feasibility testing; graft vs host disease; improved; male; mortality; neoantigens; next generation; next generation sequencing; personalized genomics; post-transplant; prediction algorithm; prognostic; prophylactic; response; risk prediction; single cell analysis; single-cell RNA sequencing; tool; tumor

Summary Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for many blood disorders but is often complicated by graft-versus-host disease (GvHD). Despite major advances in therapeutic strategies, GvHD-related morbidity and mortality remain high, and better tools to predict the GvHD risk are urgently needed. The immunologic basis of GvHD is the recognition by donor T cells of minor histocompatibility antigens (mHAgs), arising from nonsynonymous single nucleotide polymorphism (SNP) differences between donor and recipient. However, only some 50 mHAgs have been reported thus far. Current advances in the characterization of germline and somatic events within coding exomes through next-generation sequencing, coupled with improvements in HLA class I and II epitope prediction, offer an unprecedented opportunity to systematically identify candidate mHAgs on an individualized basis. We hypothesize that identification of tissue-specific mHAgs, predicted through baseline analysis of patient and donor DNA, can enable a personalized genomics-informed risk assessment of GvHD, with the potential to help refine current donor selection algorithms and to enable personalized tailoring of post-transplant immunosuppression. Our aims are thus to: (1) Build an epitope prediction pipeline to systematically identify mHAgs, incorporating state-of-the-art tools for SNP discovery from WES, expression filters designed through comprehensive analysis of single-cell RNA-seq and proteomic profiling of a set of commonly targeted GvHD tissues (i.e. skin, liver, colon and lung), inflammation signatures, and Y-chromosome specific expression (in the case of female male transplants). This will be then coupled with HLA class I and II prediction. Epitope predictions will be confirmed through direct detection of HLA-bound peptides by immunopeptidome-based evaluations of GvHD-affected target tissues. (2) Define and track the T cell responses to predicted mHAgs in patients with GvHD. To link prediction of mHAg targets with functional T cell responses, we will establish proof-of-concept by testing for mHAg-specific T cell responses across three clinically relevant settings: (i) patients experiencing organ-specific GvHD, immunoproteomically characterized in Aim 1; (ii) patients who received sequential allo-HSCT from 2 distinct HLA-identical donors and experienced GvHD following one but not the other transplant; and (iii) patients who received post-transplant cyclophosphamide after matched related donor (MRD) HSCT as part of GvHD prophylaxis. (3) Test the feasibility of mHAg prediction to generate a prognostic GvHD risk score. To determine if individual mHAg burden relates to clinically observed GvHD, we will focus on patients with myeloid neoplasia, and perform WES analysis on a discovery set of DNA from ~200 MRD recipient-donor pairs from patients treated at DFCI, and then on an extension set of ~200 pairs from URD HSCT, from whom information regarding GvHD occurrence is available. Through a planned validation analysis of ~600 other pairs (also myeloid neoplasia) from CIBMTR, we will assess if this approach is applicable cross-institutionally, and for patients across ethnicities.

概括 异基因造血干细胞移植（allo-HSCT）可能治愈许多血液疾病 但常常因移植物抗宿主病（GvHD）而变得复杂。尽管治疗策略取得了重大进展， GvHD 相关的发病率和死亡率仍然很高，迫切需要更好的工具来预测 GvHD 风险。 GvHD 的免疫学基础是供体 T 细胞对次要组织相容性抗原 (mHAgs) 的识别， 由供体和受体之间的非同义单核苷酸多态性（SNP）差异引起。 然而，迄今为止仅报道了约 50 mHAg。当前表征的进展 通过下一代测序，结合编码外显子组内的种系和体细胞事件 HLA I 类和 II 类表位预测的改进，提供了前所未有的机会来系统地 根据个体情况确定候选 mHAg。我们假设组织特异性 mHAgs 的鉴定， 通过对患者和供体 DNA 进行基线分析进行预测，可以实现个性化的基因组学信息 GvHD 风险评估，有可能帮助完善当前的捐赠者选择算法并实现 移植后免疫抑制的个性化定制。因此，我们的目标是：（1）构建表位 系统识别 mHAgs 的预测流程，结合最先进的 SNP 发现工具 来自 WES，通过单细胞 RNA-seq 和蛋白质组学综合分析设计的表达过滤器 分析一组常见目标 GvHD 组织（即皮肤、肝脏、结肠和肺）、炎症特征、 和 Y 染色体特异性表达（在女性→男性移植物的情况下）。然后这将与 HLA I 类和 II 类预测。表位预测将通过直接检测 HLA 结合来确认 通过对受 GvHD 影响的靶组织进行基于免疫肽组的评估来评估肽。 (2) 定义并跟踪T GvHD 患者中细胞对预测 mHAgs 的反应。将 mHAg 目标的预测与功能联系起来 T 细胞反应，我们将通过测试三个方面的 mHAg 特异性 T 细胞反应来建立概念验证 临床相关环境：(i) 经历器官特异性 GvHD 的患者，其免疫蛋白质组学特征为 目标1； (ii) 接受来自 2 位不同 HLA 相同供者的序贯异基因 HSCT 且经历过的患者 一次移植后发生 GvHD，但另一次移植后则不然； (iii) 接受移植后的患者 作为 GvHD 预防的一部分，匹配相关供体 (MRD) HSCT 后使用环磷酰胺。 (3) 测试 mHAg 预测生成预后 GvHD 风险评分的可行性。确定单个 mHAg 是否 负担与临床观察到的 GvHD 相关，我们将重点关注骨髓瘤患者，并进行 WES 对来自 DFCI 治疗患者的约 200 个 MRD 受体-供体对的一组 DNA 进行分析，然后 来自 URD HSCT 的约 200 对扩展组，其中有关 GvHD 发生的信息是 可用的。通过对来自 CIBMTR 的约 600 个其他对（也是骨髓瘤）进行的计划验证分析，我们 将评估这种方法是否适用于跨机构以及跨种族的患者。