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 同种异体造血干细胞移植（Allo-HSCT）对于许多血液疾病有可能治愈 但通常因移植物抗宿主病（GVHD）而变得复杂。尽管在治疗策略方面取得了重大进展，但 与GVHD相关的发病率和死亡率仍然很高，并且迫切需要更好地预测GVHD风险的工具。 GVHD的免疫学基础是供体T细胞对较小的组织相容性抗原（MHAGS）的识别， 供体和受体之间的非同义单核苷酸多态性（SNP）差异引起。 但是，到目前为止，仅报告了约50个MHAG。当前表征的进步 通过下一代测序在编码外组中的种系和躯体事件，并与 HLA I和II级表位预测的改进，为系统地提供了前所未有的机会 在个性化的基础上确定候选人MHAG。我们假设鉴定组织特异性MHAG， 通过对患者和供体DNA的基线分析进行预测，可以启用个性化的基因组知识。 GVHD的风险评估，有可能帮助完善当前的捐助者选择算法并启用 移植后免疫抑制的个性化剪裁。因此，我们的目标是：（1）建立一个表位 预测管道系统地识别MHAG，并包含用于SNP发现的最新工具 来自WES，通过对单细胞RNA-Seq和蛋白质组学的全面分析设计的表达过滤器 分析一组常见靶向的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（对于雌性雄性移植）。然后将与 HLA I类和II的预测。表位预测将通过直接检测HLA结合来确认 基于免疫肽组的肽对受GVHD影响的靶组织的评估。 （2）定义和跟踪t 细胞对GVHD患者的预测MHAG的反应。将MHAG目标的预测与功能联系起来 T细胞响应，我们将通过测试三个MHAG特异性T细胞响应来建立概念概念 临床相关设置：（i）经历特定器官特异性GVHD的患者免疫蛋白质表征 目标1; （ii）从2个不同的HLA供体和经验丰富的患者 GVHD遵循一次但不遵循另一个移植； （iii）接受移植后的患者 匹配相关供体（MRD）HSCT后的环磷酰胺作为GVHD预防的一部分。 （3）测试 MHAG预测产生预后GVHD风险评分的可行性。确定是否单个MHAG 与临床观察到的GVHD的负担关系，我们将重点关注髓样肿瘤的患者，并进行WES 分析来自DFCI治疗的患者的约200个MRD受体DONOR对的DNA集合，然后 从乌尔德·赫斯克（URD HSCT）的约200对扩展集中，有关GVHD发生的信息是 可用的。通过CIBMTR的〜600对（也是髓样肿瘤）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。