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T cell invasion of the stem cell compartment during immune-mediated GI damage

免疫介导的胃肠道损伤过程中 T 细胞入侵干细胞区室

基本信息

批准号：
10542401
负责人：
Alan M Hanash
金额：
$ 57.3万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542401
关键词：
3-Dimensional Active immunity Acute Graft Versus Host Disease Address Adoptive Cell Transfers Affect Allogeneic Bone Marrow Transplantation Allogenic Automobile Driving Behavior Biological Biology Bone Marrow Transplantation Cell Adhesion Molecules Cell Communication Cell Compartmentation Cells Clinical Coculture Techniques Development Endothelium Enterocytes Environment Epithelium Frequencies Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Genetic Techniques Genetic Transcription Goals Hematopoietic Homeostasis Homing Homologous Transplantation Human Immune Immune Targeting Immune response Immune system Immunity Immunologics Immunology Immunosuppression In Situ Individual Infiltration Inflammatory Bowel Diseases Intervention Intestinal Mucosa Intestines Invaded LGR5 gene Ligands Location Lymphocyte Lymphoid Cell Maintenance Measures Mediating Memorial Sloan-Kettering Cancer Center Microscopy Modeling Molecular Mucous Membrane Natural regeneration Organoids Paneth Cells Pathogenicity Pathologic Pathology Pathway interactions Phenotype Physiological Process Publishing Recovery Regulation Research Proposals Resources Role Sampling Science Signal Transduction Site T cell infiltration T-Cell Activation T-Lymphocyte Testing Therapeutic Thick Three-Dimensional Imaging Tissues Toxic effect Transplantation Transplantation Conditioning Validation base cell injury cell motility chemokine clinically significant conditioning crypt cell dimer epithelial injury epithelial stem cell epithelium regeneration gastrointestinal genetic manipulation graft vs host disease hematopoietic transplantation human model immune imaging immune system function immunopathology in vivo in vivo Model injury recovery insight interleukin-22 intestinal injury intravital imaging man microscopic imaging migration mouse model multidisciplinary novel novel therapeutics post-transplant protein expression recruit response skills stem cell biology stem cells targeted treatment tissue regeneration translational immunology translational model translational potential transplant model two-photon

项目摘要

Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance in the gastrointestinal (GI) tract and the clinical significance of inflammatory intestinal disorders and immune-mediated GI damage, the potential of the immune system to directly engage with the ISC compartment remains poorly understood. GI graft vs. host disease (GVHD) is one of the greatest challenges for allogeneic hematopoietic/bone marrow transplantation (allo-BMT), causing severe toxicity, necessitating deeply immunosuppressive interventions, and limiting the wider usage of allo-BMT for potentially curable conditions. We have found that acute GVHD leads to substantial reduction of Lgr5+ ISCs and the Paneth cells providing their epithelial niche. While there is limited understanding of the precise mechanisms by which immune responses induce ISC compartment damage and regeneration, it is not possible to fully understand BMT-related complications in the GI tract or how immune cells may impact specific epithelial components without examining the three-dimensional (3-D) tissue environment of the intestines and the proximity of immune responses to the ISC compartment. We seek to understand the fundamental interactions occurring between the immune system and the ISC compartment, how these interactions are engaged in the context of hematopoietic transplantation, and how the underlying biology may be manipulated therapeutically for clinical intervention. To address these goals, we have developed a research proposal emphasizing 3-D imaging of immune effectors within GI tract, mechanistic ex vivo modeling of murine and human immune cell recruitment to the ISC compartment, and in vivo validation in experimental transplant models. We have also assembled a multi-disciplinary team of collaborators at the forefront of basic and translational immunology, ISC biology, and advanced microscopic imaging. Our preliminary findings indicate that the ISC compartment is the first site of allogeneic T cell invasion within the intestinal mucosa after BMT and thus the initial target of GVHD. Furthermore, we have found that co-cultures of immune cells and intestinal organoids can be used to model and mechanistically dissect these processes. Using 3-D confocal and 2-photon intravital imaging, we have developed the capacity to accurately quantify loss of ISCs, specific invasion of the ISC compartment, and localization of T cell homing ligands during homeostasis and during active immunity. We have also developed strategies for analysis of in vivo lineage- specific gene expression within the ISC compartment. This study will thus test the hypothesis that lymphocyte recruitment to and regulation of the ISC compartment are central features of GI damage post-transplant, impacting both physiologic and pathologic mucosal responses, and we will evaluate approaches to modulate lymphocyte homing and promote recovery of injured epithelium. This project will lead to a mechanistic understanding of fundamental interactions between the ISC compartment and the immune system, opening a new direction for treatment of GVHD and other GI disorders by protecting ISCs and augmenting regeneration.

尽管肠干细胞(ISCs)对胃肠道(GI)上皮的维持很重要以及炎症性肠道疾病和免疫介导的胃肠道损伤的临床意义，免疫系统直接与ISC隔室接触的潜力仍然知之甚少。美国退伍军人协会移植物抗宿主病(GVHD)是异基因造血/骨髓面临的最大挑战之一移植(allo-BMT)，造成严重毒性，需要深度免疫抑制干预，以及限制allo-BMT在潜在可治愈条件下的更广泛使用。我们发现急性移植物抗宿主病先导导致Lgr5+ISCs和Paneth细胞显著减少，为其提供上皮龛。在有限的时间里了解免疫反应导致ISC间隔室损伤和再生，不可能完全了解胃肠道的骨髓移植相关并发症或如何免疫细胞可能会影响特定的上皮成分，而不检查三维(3-D)组织肠道环境和免疫反应对ISC隔间的接近程度。我们寻求了解免疫系统和ISC之间发生的基本相互作用，这些相互作用是如何在造血移植的背景下进行的，以及潜在的生物学可以在治疗上被操纵，用于临床干预。为了实现这些目标，我们有开发了一项研究方案，强调胃肠道内免疫效应器的3D成像，机械性试验小鼠和人类免疫细胞募集到ISC隔室的活体模型，并在体内验证实验性移植模型。我们还组建了一个由多学科合作伙伴组成的团队，基础免疫学和翻译免疫学、ISC生物学和高级显微成像的前沿。我们的初步研究结果表明，ISC室是同种异体T细胞入侵的第一个部位骨髓移植后的肠粘膜，因此是移植物抗宿主病的最初靶点。此外，我们还发现，共同文化免疫细胞和肠道类器官可以用来模拟和机械地剖析这些过程。使用三维共聚焦和双光子活体成像，我们已经开发了准确量化损失的能力间充质干细胞的特异性侵袭，以及T细胞归巢配体的定位动态平衡和主动免疫期间。我们还开发了分析体内血统的策略- 在ISC间隔内的特定基因表达。因此，这项研究将检验淋巴细胞移植后胃肠道损伤的主要特征是ISC的募集和调节。影响生理和病理黏膜反应，我们将评估调节方法淋巴细胞归巢，促进受损上皮的修复。这个项目将导致一个机械化的了解ISC间隔和免疫系统之间的基本相互作用，打开了一个通过保护ISCs和增强再生来治疗GVHD和其他胃肠道疾病的新方向。