Novel Biologic Therapies for BMT: Mechanistic Evaluation in Rhesus Macaques

摘要： 造血干细胞移植(Hct)是一种挽救生命的疗法，但仍受到 并发症，最致命的是移植物抗宿主病(GVHD)。急性移植物抗宿主病发生在 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，特别是涉及胃肠道系统的GVHD，往往无法治疗，导致高发病率 HCT后的发病率和死亡率。这些问题在该领域引发了三个核心挑战。它们是：(1) 驱动突破T细胞同种免疫和组织损伤的机制是什么 免疫抑制策略？(2)我们能设计直接针对这些机制的治疗策略吗？ 以及(3)预防GVHD战略的必要组成部分是什么，才能安全地产生长期 免疫耐受？为了解决这些问题，我们开发并提炼了唯一的非人类灵长类动物 (NHP)模型，并利用该模型发现了一系列有关GVHD免疫学的新见解。 这种病。其中包括：(1)系统生物学方法可以应用于GVHD，以揭示中枢 机制和目标路径。(2)AGVHD可分为“初级阶段”和“突破期” 机制：原发GVHD由Th/Tc1途径驱动，突破性GVHD由IL17- 优势路径。(3)无钙调神经磷酸酶抑制剂可成功控制原发性AGVHD CD28：CD80/86阻断+雷帕霉素。这些发现构成了我们对AGVHD的新理解的核心 并通知我们下一阶段的工作。这项研究是基于最重要的假设，即组织- 可以确定控制GVHD的特定分子机制，通过靶向这些机制， 预防和治疗这种疾病的循证方法是可以实现的。我们将对此进行测试 假设通过以下具体目标：目标1：以证据为基础的GVHD预防：这一目标将 确定通过转录组分析确定的免疫逃逸途径的策略 旨在预防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 NHP GVHD期间血液-肝脏和胃肠道特异性免疫激活的转录图谱，使用两者 群体和单细胞技术。目标3：循证GVHD治疗：在这一目标中，我们将 确定在NHP和患者中控制突破性GVHD的机制并测试新的 我们新开发的NHP GVHD治疗模式的治疗策略。

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.