Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques

BMT 的新型生物疗法：恒河猴的机制评估

• 批准号: 9358731
• 负责人: Leslie S Kean
• 金额: $ 67.28万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358731
• 关键词: Acute Graft Versus Host Disease; Address; Biological Assay; Biological Response Modifier Therapy; Biology; Blood; CD28 gene; CD80 gene; Calcineurin inhibitor; Cells; Clinical; Clinical Trials; Clonal Expansion; Data; Diagnostic; Disease; Evaluation; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Transplantation; IL17 gene; Immune; Immune Cell Activation; Immune Tolerance; Immunobiology; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Investigation; Lead; Life; Liver; Macaca mulatta; Maps; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Movement; Non-Malignant; Organ; PPBP gene; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Population; Prevention approach; Prevention strategy; Procedures; Public Health; RNA; Research; STK6 gene; Savings; Series; Sirolimus; System; Systems Biology; T-Lymphocyte; Techniques; Testing; Tissues; Transplant Recipients; Work; aurora-A kinase; base; biobank; chronic graft versus host disease; design; disorder control; disorder prevention; evidence base; graft vs host disease; immune activation; improved; in vivo; insight; isoimmunity; mortality; next generation; nonhuman primate; novel; novel strategies; novel therapeutics; prevent; success; targeted treatment; therapy design; transcriptome; transcriptomics; translational pipeline; treatment strategy

ABSTRACT: Hematopoietic stem cell transplantation (HCT) is a life-saving therapy, but one that is still plagued with complications, the most deadly of which is graft-versus-host disease (GVHD). Acute GVHD (AGVHD) occurs in as many as 70% of transplant recipients, despite their treatment with multiple immunosuppressive drugs. Moreover, Grade III-IV GVHD, especially involving the GI system, is often untreatable, leading to high rates of post-HCT morbidity and mortality. These issues give rise to three central challenges in the field. They are: (1) What are the mechanisms that drive breakthrough T cell allo-immunity and tissue damage despite current immune suppression strategies? (2) Can we design treatment strategies to directly target these mechanisms? and (3) What are the necessary components of a GVHD-prevention strategy that will safely produce long-term immune tolerance? To address these questions, we have developed and refined the only non-human primate (NHP) model of GVHD, and have used this model to discover a series of new insights into the immunology of this disease. These include: (1) That a systems biology approach can be applied to GVHD to uncover central mechanisms and targetable pathways. (2) That AGVHD can be divided into “primary” and “breakthrough” mechanisms: with primary GVHD driven by Th/Tc1 pathways, while breakthrough GVHD is driven by IL17- predominant pathways. (3) That primary AGVHD can be successfully controlled by calcineurin Inhibitor-free CD28:CD80/86 blockade + rapamycin. These discoveries form the core of our new understanding of AGVHD and inform the next phase of our work. This work is based on the overarching hypothesis that the tissue- specific molecular mechanisms controlling GVHD can be identified, and that by targeting these mechanisms, an evidence-based approach to the prevention and treatment of this disease can be achieved. We will test this hypothesis through the following Specific Aims: Aim 1: Evidence-based GVHD Prevention: This Aim will determine strategies by which immune escape pathways, identified through transcriptome analysis, can be targeted to prevent GVHD. Aim 2: Tissue-Specific GVHD Diagnostics: In this Aim, we will establish a transcriptomic map comparing blood- liver, and GI-specific immune activation during NHP GVHD, using both population- and single-cell techniques. Aim 3: Evidence-based GVHD Treatment: In this Aim we will determine the mechanisms controlling breakthrough GVHD in both NHP and patients and test novel treatment strategies in our newly-developed NHP GVHD Treatment Model.

摘要： 造血干细胞移植（HCT）是一种挽救生命的治疗方法，但仍然受到 并发症，其中最致命的是移植物抗宿主病（GVHD）。急性GVHD（AGVHD）发生在 多达70%的移植受者，尽管他们接受了多种免疫抑制药物的治疗。 此外，III-IV级GVHD，特别是涉及GI系统的GVHD，通常是不可治疗的，导致高发生率。 HCT后发病率和死亡率。这些问题在实地产生了三个核心挑战。它们是：（1） 什么是驱动突破性T细胞同种异体免疫和组织损伤的机制，尽管目前 免疫抑制策略(2)我们能否设计出直接针对这些机制的治疗策略？ 和（3）什么是GVHD预防策略的必要组成部分，将安全地产生长期的 免疫耐受？为了解决这些问题，我们开发并改进了唯一一种非人类灵长类动物 (NHP)GVHD模型，并利用该模型发现了一系列对GVHD免疫学的新见解。 这种疾病。这些包括：（1）系统生物学方法可以应用于GVHD，以揭示中枢 机制和有针对性的途径。(2)认为AGVHD可分为"原发性"和"突破性" 机制：原发性GVHD由Th/Tc1途径驱动，而突破性GVHD由IL 17- 主要途径。(3)原发性AGVHD可以通过无钙调神经磷酸酶抑制剂的 CD28：CD80/86阻断+雷帕霉素。这些发现构成了我们对AGVHD新认识的核心 为我们下一阶段的工作提供信息这项工作是基于一个总体假设，即组织- 可以鉴定控制GVHD的特定分子机制，并且通过靶向这些机制， 可以采取循证方法预防和治疗这一疾病。我们将测试这个 通过以下具体目标的假设：目标1：基于证据的GVHD预防：该目标将 确定通过转录组分析鉴定的免疫逃逸途径的策略， 以预防GVHD。目标2：组织特异性GVHD诊断：在这个目标中，我们将建立一个 转录组学图谱比较NHP GVHD期间的血-肝和GI特异性免疫激活， 群体和单细胞技术。目标3：基于证据的GVHD治疗：在这个目标中，我们将 确定NHP和患者中控制突破性GVHD的机制， 在我们新开发的NHP GVHD治疗模型中，