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性造血干细胞移植的两个主要障碍 （HSCT）：移植-VS宿主病（GVHD）和复发。提出了一种新的策略，挑战 事实后，试图减少供体T细胞出色反应性的盛行练习是控制传入的一种 树突状细胞（DC）在抗原呈递水平上淋巴细胞效应子的敏化。 DCS 包括有效抗原呈递细胞的异质种群，启动免疫力和控制 它的质量。我们假设GVHD的不良并发症可以与有益的 基于免疫反应的传入敏感性差异，同种异体HSCT产生的GVL效应 通过不同的直流亚型。该假设将在以下特定目的中解决：具体目的1： 确定在体外人类Langerhans型DC（LCS）和T细胞之间的同种异体相互作用是否相互作用 通过抑制JAK2-STAT3信号传导消除，WTI mRNA-的能力是否能力 电穿孔的LCS仍然完好无损，可以通过IL15-损坏对这种自定义肿瘤Ag的耐受性。 依赖机制。特定目标2：比较和对比NK细胞中JAK2-STAT3的抑制 通过IL12P70依赖性机制，由单核细胞衍生的DC（MODC）刺激，JAK2抑制 MODC刺激的同种异体T细胞。特定目标3：评估JAK2抑制的机制 在定义的小鼠移植模型中，相对于同种反应性和肿瘤免疫。成功抑制 JAK2-PSTAT3途径，它将至少阻止MODC衍生的IL6和IL23细胞因子对 同种异体淋巴细胞将导致使用全新的药物进行预防和 GVHD的处理。这将保持免于复发（GVL）和传染性发病率和死亡率的自由 由较少选择性免疫抑制带来。该方法还将充分利用 w t i mRNA - 电载体的LCS的效力，以破坏耐受性并刺激有效的CTL 广泛表达的，自分配的肿瘤AG。成功完成这些目标将从根本上 通过控制免疫，在同种异体HSCT的背景下改变了移植物 - 宿主相互作用的管理 响应由不同的DC子集从其发作中调节。这些研究也将有更广泛的公众 健康潜力，以改善固体中免疫抑制和预防移植排斥的治疗 器官移植。