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

定义同种异体 T 细胞中介导移植物抗宿主疾病的 IL-33 信号网络

基本信息

批准号：
10357847
负责人：
Gaelen Dwyer
金额：
$ 4.99万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357847
关键词：
Address Alloantigen Allogenic Anemia Antigens Aplastic Anemia Automobile Driving Bioinformatics Blood Cells Bone Marrow Cells CD4 Positive T Lymphocytes Cell Shape Cell Survival Cells Clinical Complication Data Development Disease Disease model Donor person Experimental Designs Exposure to Foundations Future Gastrointestinal tract structure Goals Hematologic Neoplasms Hematology Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hereditary Disease Home Human Immune Immune Tolerance Immune system Immunology Interleukins Interruption Knowledge Manuscripts Mediating Mentorship Methods Morbidity - disease rate Mucous Membrane Mus Non-Malignant Oncology Organ Organ Transplantation Pathogenesis Pathogenicity Pathology Peripheral Phase Physicians Population Preparation Protocols documentation Publications Regimen Research Role Scientist Secondary to Signal Transduction Small Intestines Solid Source Stem cell transplant T cell differentiation T cell response T-Cell Activation T-Lymphocyte Techniques Testing Th1 Cells Thalassemia Tissues Training Transgenic Mice Universities Work base career career development cell injury cell motility chemotherapy conditioning donor stem cell effector T cell gastrointestinal graft vs host disease inflammatory milieu insight interest irradiation isoimmunity migration mortality mouse model novel pathogen prevent programs receptor response secondary lymphoid organ sickling skills symposium targeted treatment trafficking transcriptomics

项目摘要

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.

移植物抗宿主病（GVHD），其中供体T细胞识别并破坏表达同种异体抗原的宿主组织，是异基因干细胞移植（alloSCT）的主要并发症，限制了alloSCT作为一种更好的治疗方法的使用。广泛应用的治疗。需要更多地了解驱动供体T细胞介导的GVHD的机制更好地了解如何预防或解决GVHD。为捐赠者的干细胞创造空间，为了防止它们被宿主免疫细胞快速排斥，alloSCT方案去除了受体的免疫系统，造血干细胞与包括化学疗法和/或辐射的预处理方案。这些治疗损害屏障组织，包括小肠（SI），并刺激白细胞介素的释放（IL）-33。虽然GVHD的独特之处在于抗原总是存在，但GVHD的发病机制可能与GVHD有关。 T细胞介导的疾病遵循次级淋巴器官（SLO）中T细胞活化的范例以及迁移到在调节方案之后存在组织损伤的屏障组织。有趣的是， IL-33在粘膜屏障组织和SLO中均有表达。然而，目前尚不清楚受体屏障是否组织、SLO或两者都是GVHD中致病性IL-33的关键来源。因此，我假设IL-33 促进GVHD，因为它首先放大SLO中的早期激活和分化，然后维持SLO中的GVHD。 GVHD靶组织中的同种异体CD 4 + T细胞效应物。我将通过解决以下问题来检验这一假设具体目标：1。定义早期缺乏IL-33刺激同种异体反应性CD 4 + T细胞如何形成活化， SLO中的增殖和分化; 2.确定是否中断晚期ST 2信号传导至供体CD 4 + Th 1细胞限制它们在GVHD靶组织中的持久性并阻止GVHD。随着这些目标的成功实现，我将确定IL-33如何影响SLO中的CD 4 + T细胞活化并影响CD 4 + T细胞存活， alloSCT后GVHD期间SI的持续性。这些研究将提供新的见解，促进和维持同种异体免疫和GVHD。这些研究还将阐明，如果中和IL-33或中断 SLO或SI中的ST 2信号传导的抑制是用于预防或解决GVHD的靶向疗法。贡献培训：该提案描述了一个独特的培训计划，结合了对GVHD发病机制的研究，通过在会议上的演讲，提供生物信息学培训和专业发展的同种免疫和手稿准备。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的著名研究项目，是成功职业生涯的坚实基础作为一个学术医生科学家。