Defining the IL-33 signaling networks in allogeneic T cells that mediate graft vs. host disease

项目摘要/摘要 移植物抗宿主病(GVHD)，供者T细胞识别并摧毁表达同种异体抗原的宿主组织， 是异基因干细胞移植(AllSCT)的一个主要并发症，限制了异基因干细胞移植的使用 广泛应用的疗法。需要更多地了解供者T细胞介导的移植物抗宿主病的机制 以便更好地了解如何预防或解决移植物抗宿主病。为捐赠者干细胞创造空间并 防止宿主免疫细胞的快速排斥，异基因干细胞移植方案移除受者的免疫系统，并 造血干细胞与包括化疗和/或放射在内的调理方案。这些 治疗会损害屏障组织，包括小肠(SI)，并刺激白细胞介素2的释放 (IL)-33来源于GVHD靶组织。虽然GVHD的独特之处在于总是存在抗原，但GVHD的发病机制 T细胞介导的疾病遵循次级淋巴器官(SLO)中T细胞激活的范例 和迁移到屏障组织，其中有组织损伤后的条件化方案。有趣的是， IL-33在黏膜屏障组织和SLO中均有表达。然而，目前尚不清楚接受者是否会遇到障碍 组织、SLO或两者都是GVHD致病IL-33的重要来源。因此，我假设IL-33 促进移植物抗宿主病，因为它首先放大SLO的早期激活和分化，然后维持 移植物抗宿主病靶组织中的同种异体CD4+T细胞效应因子。我将通过解决以下问题来验证这一假设 具体目标：1.确定早期缺乏IL-33刺激的同种反应性CD4+T细胞如何影响激活， SLO中的增殖和分化；2.确定是否阻断供者CD4+Th1细胞的晚期ST2信号 限制它们在GVHD靶组织中的持久性，并阻止GVHD。随着这些目标的圆满完成， 我将确定IL-33如何影响SLO中CD4+T细胞的激活，以及如何影响CD4+T细胞的存活和 异基因SCT后GVHD期间SI持续存在。这些研究将提供新的见解，以了解警报是如何 促进和维持同种免疫和移植物抗宿主病。这些研究还将阐明中和IL-33或干扰 SLO或SI的ST2信号转导是预防或解决移植物抗宿主病的靶向治疗方法。对以下项目的贡献 培训：本建议描述了一种独特的培训计划，该计划结合了GVHD发病机制和 同种异体免疫与生物信息学培训和专业发展通过在会议上的演讲 和手稿准备。这项工作将我在血液学和肿瘤学方面的临床兴趣与 匹兹堡大学著名的研究项目，是成功职业生涯的坚实基础 作为一名学术内科科学家。

PROJECT SUMMARY/ABSTRACT Graft vs. host disease (GVHD), where donor T cells recognize and destroy alloantigen-expressing host tissues, is a major complication of allogeneic stem cell transplantation (alloSCT) limiting the use of alloSCT as a more widely applied therapy. Greater knowledge of the mechanisms driving donor T cell-mediated GVHD is needed to provide a better understanding of how to prevent or resolve GVHD. To create space for donor stem cells and prevent their rapid rejection by host immune cells, alloSCT protocols remove the recipient’s immune system and hematopoietic stem cells with conditioning regimens including chemotherapy and/or irradiation. These treatments damage the barrier tissues, including the small intestine (SI), and stimulate the release of interleukin (IL)-33 from GVHD target tissue. While GVHD is unique in that antigen is always present, the pathogenesis of the T cell mediated disease follows the paradigm of T cell activation in the secondary lymphoid organs (SLO) and migration to the barrier tissue where there is tissue damage following conditioning regimens. Interestingly, IL-33 is expressed both in the mucosal barrier tissues and SLO. Yet, it is unknown whether recipient barrier tissues, SLO, or both are the critical source of pathogenic IL-33 in GVHD. Therefore, I hypothesize that IL-33 promotes GVHD because it first amplifies early activation and differentiation in the SLO and then sustains allogeneic CD4+ T cell effectors in the GVHD target tissues. I will test this hypothesis by addressing the following Specific Aims: 1. Define how an early lack of IL-33 stimulation of alloreactive CD4+ T cells shapes activation, proliferation and differentiation in the SLO; 2. Determine if interrupting late ST2 signaling to donor CD4+ Th1 cells limits their persistence in the GVHD target tissues and stops GVHD. With successful completion of these aims, I will establish how IL-33 impacts CD4+ T cell activation in the SLO and influences CD4+ T cell survival and persistence in the SI during GVHD after alloSCT. These studies will provide new insights into how alarmins promote and sustain alloimmunity and GVHD. These studies will also elucidate if neutralizing IL-33 or interruption of ST2 signaling in the SLO or SI is a targetable therapy for preventing or resolving GVHD. Contribution to Training: This proposal describes a unique training plan combining research in the pathogenesis of GVHD and alloimmunity with bioinformatics training and professional development through presentations at conferences and manuscript preparation. This work integrates my clinical interests in hematology and oncology with renowned research programs at the University of Pittsburgh and is a strong foundation for a successful career as an academic physician scientist.