Distinquishing the Afferent Sensitization of GVHD from GVL/GVT at the Level of H

在 H 水平上区分 GVHD 和 GVL/GVT 的传入敏化

• 批准号: 9067216
• 负责人: James William Young
• 金额: $ 30.54万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9067216
• 关键词: Address; Allogenic; Allografting; Antigen Presentation; Antigen-Presenting Cells; Blood; Dendritic Cells; Freedom; Graft Rejection; Hematopoietic Stem Cell Transplantation; Human; IL6 gene; Immune; Immune response; Immunity; Immunobiology; Immunosuppression; In Vitro; Instruction; Interleukin-15; JAK2 gene; Lead; Lymphocyte; Marrow; Messenger RNA; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Organ Transplantation; Pathway interactions; Pharmaceutical Preparations; Population Heterogeneity; Prevention; Public Health; Reaction; Relapse; STAT3 gene; Signal Transduction; Solid; Stem cell transplant; T-Lymphocyte; Transplant Recipients; Transplantation; Tumor Immunity; base; cytokine; graft vs host disease; graft vs leukemia effect; improved; in vivo; leukemia; monocyte; mortality; novel strategies; prevent; tumor

This project addresses two major barriers to progress in allogeneic hematopoietic stem cell transplantation (HSCT): graft-vs-host disease (GvHD) and relapse. A novel strategy is proposed that challenges the prevailing practice of trying to curtail donor T cell alloreactivity after the fact, to one of controlling the afferent sensitization of lymphocyte effectors at the level of antigen-presentation by dendritic cells (DCs). DCs comprise a heterogeneous population of potent antigen-presenting cells, which initiate immunity and control its quality. We hypothesize that the undesirable complications of GvHD can be separated from the beneficial GvL effects exerted by allogeneic HSCT, based on differences in afferent sensitization of immune responses by distinct DC subtypes. This hypothesis will be addressed in the following specific aims: SPECIFIC AIM 1: Determine whether allogeneic interactions between human Langerhans-type DCs (LCs) and T cells in vitro are abrogated by inhibition of JAK2-STAT3 signaling, and whether the capacity of WTI mRNA- electroporated LCs remains intact to break tolerance against this self-differentiation tumor Ag by an IL15- dependent mechanism. SPECIFIC AIM 2: Compare and contrast the inhibition of JAK2-STAT3 in NK cells stimulated by monocyte-derived DCs (moDCs) via an IL12p70-dependent mechanism, with JAK2 inhibition of moDC-stimulated allogeneic T cells. SPECIFIC AIM 3: Evaluate the mechanism of JAK2 inhibition with respect to alloreactivity and tumor immunity in defined mouse transplant models. Successful inhibition of the JAK2-pSTAT3 pathway, which would block at least moDC-derived IL6 and IL23 cytokine effects on alloreactive lymphocytes, would lead to the use of an entirely new class of drugs for prevention and treatment of GvHD. This would maintain freedom from relapse (GvL) and infectious morbidity and mortality brought on by less selective immune suppression. The approach would also take full advantage of the potency of W T I mRNA-electroporated LCs to break tolerance and stimulate effective CTLs against this broadly-expressed, self-differentiation tumor Ag. Successful completion ofthese aims will fundamentally alter management of graft-host interactions in the context of allogeneic HSCT by controlling immune responses regulated by distinct DC subsets from their onset. These studies will also have broader public health potential to improve management of immune suppression and prevention of graft rejection in solid organ transplantation.

该项目解决了同种异体造血干细胞移植进展的两大障碍 （HSCT）：移植物抗宿主病（GvHD）和复发。提出了一项新颖的战略，挑战 事后试图减少供体 T 细胞同种异体反应性的普遍做法是控制传入细胞之一 树突状细胞（DC）在抗原呈递水平上使淋巴细胞效应器致敏。 DCs 包含强效抗原呈递细胞的异质群体，可启动免疫和控制 它的质量。我们假设 GvHD 的不良并发症可以与有益的并发症区分开来。 基于免疫反应传入敏化的差异，同种异体 HSCT 产生的 GvL 效应 通过不同的 DC 亚型。该假设将在以下具体目标中得到解决：具体目标 1： 体外确定人朗格汉斯型 DC (LC) 与 T 细胞之间是否存在同种异体相互作用 通过抑制 JAK2-STAT3 信号传导而消除，以及 WTI mRNA 的能力是否 电穿孔的 LC 保持完整，以打破 IL15-对这种自我分化肿瘤 Ag 的耐受性 依赖机制。具体目标 2：比较和对比 NK 细胞中 JAK2-STAT3 的抑制作用 通过 IL12p70 依赖性机制受到单核细胞衍生 DC (moDC) 的刺激，并抑制 JAK2 moDC 刺激的同种异体 T 细胞。具体目标 3：评估 JAK2 抑制机制 关于特定小鼠移植模型中的同种反应性和肿瘤免疫。成功抑制 JAK2-pSTAT3 通路，至少会阻断 moDC 衍生的 IL6 和 IL23 细胞因子对 同种异体反应性淋巴细胞，将导致使用一类全新的药物来预防和治疗 GvHD 的治疗。这将保持无复发（GvL）和感染发病率和死亡率 由较少选择性的免疫抑制引起。该方法还将充分利用 W T I mRNA 电穿孔 LC 打破耐受性并刺激有效 CTL 的效力 广泛表达的、自我分化的肿瘤Ag。这些目标的顺利完成将从根本上 通过控制免疫改变同种异体 HSCT 背景下移植物-宿主相互作用的管理 反应从一开始就受到不同 DC 子集的调节。这些研究也将得到更广泛的公众关注 改善免疫抑制管理和预防实体移植排斥反应的健康潜力 器官移植。