Alloreactive and autoreactive immune-mediated mechanisms of impaired epithelial regeneration in the GI tract

胃肠道上皮再生受损的同种反应性和自身反应性免疫介导机制

基本信息

批准号：
9770648
负责人：
Alan M Hanash
金额：
$ 63.85万
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：
2018
资助国家：
美国
起止时间：
2018-08-25 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9770648
关键词：
3-Dimensional Acute Acute Graft Versus Host Disease Affect Allogeneic Bone Marrow Transplantation Autoimmunity Biological Biology Blood Vessels Cell Adhesion Molecules Cell Communication Cell Compartmentation Cell Count Cell model Cell physiology Cells Cessation of life Coculture Techniques Collaborations Data Development Disease Environment Epithelial Epithelial Cells Epithelium Failure Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Genetic Transcription Histology Homeostasis Homing Human Immune Immune Targeting Immune response Immune signaling Immune system Immunology Immunotherapy Impairment Infiltration Inflammatory Injury Integrins Intestinal Diseases Intestines LGR5 gene Ligands Location Measures Mediating Memorial Sloan-Kettering Cancer Center Microscopy Modeling Mucous Membrane Mus National Institute of Diabetes and Digestive and Kidney Diseases Natural regeneration Organoids Paneth Cells Pathogenicity Pathologic Pathology Pathway interactions Process Published Comment Recovery Regulation Regulatory T-Lymphocyte Resources Role Sampling Stem cells T cell regulation T-Cell Depletion T-Lymphocyte Testing Therapeutic Three-Dimensional Imaging Tissues Tumor-infiltrating immune cells Up-Regulation autoreactivity biobank cell dedifferentiation cell injury clinically relevant crypt cell dimer effector T cell experience gastrointestinal graft vs host disease imaging approach immunopathology immunoregulation in vivo in vivo Model in vivo evaluation in vivo regeneration injured insight interleukin-22 intestinal epithelium man migration mouse model mucosal addressin cell adhesion molecule-1 multidisciplinary novel novel therapeutics protein expression receptor recruit regenerative response skills stem cell biology systemic autoimmunity tissue regeneration translational model

项目摘要

The extent to which intestinal stem cells (ISCs) are targeted and depleted during immune-mediated gastro- intestinal (Gl) damage and the role of the immune system in regulating ISC-mediated regeneration are poorly understood. Likewise, while T cells are known to migrate to the intestines, their specific localization within the tissue and proximity to the ISC compartment when mediating disease are largely unknown. In collaboration with the NIDDK-sponsored Intestinal Stem Cell Consortium, this proposal assembles a multi-disciplinary team to elucidate how the immune system can influence the ISC compartment during intestinal damage and regeneration, as well as to evaluate approaches to overcome such damage and promote recovery of injured epithelium. Our preliminary findings indicate that ISCs and their ability to mediate regeneration are lost during both alloreactive injury from graft vs. host disease (GVHD) and autoreactive injury from regulatory T cell depletion, and that co-cultures of immune cells and gut organoids can be used to model and mechanistically dissect these processes. We have also found that Interleukin-22 (IL-22) is an important signal from the immune system augmenting ISC-mediated regeneration after injury. New preliminary data developed in response to reviewer comments indicate that our autoimmunity model mirrors GVHD with acute activation of effector T cells and upregulation of GI homing molecules, infiltration of the GI tract with activated T cells, and reduced epithelial damage after IL-22 treatment. F-652, a novel rhIL-22 dimer developed by Generon Corp., has translational potential to promote ISC recovery and epithelial regeneration in vivo. Additional new data demonstrate that our 3-D imaging approach can quantify loss of ISCs, specific invasion of the ISC compartment, and localization of vascular integrin ligands in GVHD. New mechanistic data indicate that MAdCAM-1 blockade specifically inhibits T cell crypt invasion and protects ISCs, indicating this pathway to be an important regulator of ISC injury, and not just overall gut migration. We will test the hypotheses that 1) T cell recruitment to the ISC compartment, depletion of ISCs, and loss of their regenerative capacity are common features of immune-mediated epithelial injury in the GI tract and 2) IL- 22 administration can protect ISCs and promote regeneration after damage. ISC function and depletion will be evaluated with autoreactive and alloreactive experimental approaches, utilizing in vivo mouse models of systemic autoimmunity and GVHD as well as ex vivo cultures of mouse and human intestinal organoids in collaboration with UMC Utrecht, their organoid biobank, and their advanced ISC expertise. IL-22 treatment will be evaluated as an epithelial-targeted regenerative immunotherapy promoting ISC function. No therapy exists currently to accelerate GI recovery from immunopathology. 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 inflammatory GI diseases by protecting ISCs and augmenting regeneration.

在免疫介导的胃 - 肠道损伤和免疫系统在调节ISC介导的再生中的作用很差理解。同样，尽管已知T细胞迁移到肠道，但它们在肠中的特定定位介导疾病时，组织和与ISC隔室的接近是未知的。合作通过NIDDK赞助的肠道干细胞财团，该提案组成了一个多学科团队阐明免疫系统如何在肠道损伤和再生，以及评估克服这种损害并促进受伤的方法的方法上皮。我们的初步发现表明，ISC及其介导的能力在嫁接与宿主疾病（GVHD）的同种异体损伤和调节性T细胞的自动损伤耗尽，免疫细胞和肠道器官的共同培养可用于建模和机械化解剖这些过程。我们还发现白介素22（IL-22）是免疫的重要信号受伤后系统增强ISC介导的再生。根据响应的新初步数据审阅者评论表明，我们的自身免疫模型反映了GVHD，急性激活效应T细胞胃肠道归巢分子的上调，用活化的T细胞浸润胃肠道，并减少 IL-22治疗后上皮损伤。 F-652是Generon Corp.开发的一种新颖的RHIL-22二聚体转化潜力，以促进体内ISC恢复和上皮再生。其他新数据证明我们的3-D成像方法可以量化ISC的损失，特定的ISC侵入 GVHD中血管整合素配体的隔室和定位。新的机械数据表明 MADCAM-1封锁专门抑制T细胞隐窝入侵并保护ISC，表明该途径为 ISC损伤的重要调节剂，而不仅仅是整体肠道迁移。我们将检验以下假设，即1）T细胞募集到ISC室，ISC的耗竭和丢失它们的再生能力是胃肠道中免疫介导的上皮损伤的常见特征和2）IL- 22管理可以保护ISC并在破坏后促进再生。 ISC功能和耗竭将是使用自动反应性和同种异体反应性实验方法进行评估，利用体内小鼠模型全身自身免疫和GVHD以及小鼠和人肠癌的离体培养物与UMC Utrecht，Organsoid Biobank及其先进的ISC专业知识的合作。 IL-22治疗将被评估为靶向上皮的再生免疫疗法促进ISC功能。不存在治疗目前是从免疫病理学加速胃肠道。这个项目将导致机械了解ISC隔室与免疫系统之间的基本相互作用通过保护ISC并增加再生来治疗炎症性胃肠道疾病的新方向。