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

• 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
• 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

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.

免疫介导的胃肠道干细胞（ISC）被靶向和耗尽的程度 肠道（GI）损伤和免疫系统在调节 ISC 介导的再生中的作用很差 明白了。同样，虽然已知 T 细胞会迁移到肠道，但它们在肠道内的特定定位 介导疾病时的组织和 ISC 区室的接近程度在很大程度上是未知的。合作中 该提案与 NIDDK 赞助的肠道干细胞联盟组建了一个多学科团队 阐明免疫系统在肠道损伤期间如何影响 ISC 区室，以及 再生，以及评估克服此类损害和促进受伤者康复的方法 上皮。我们的初步研究结果表明，ISC 及其介导再生的能力在 移植物抗宿主病 (GVHD) 引起的同种反应性损伤和调节性 T 细胞引起的自身反应性损伤 消耗，并且免疫细胞和肠道类器官的共培养可用于建模和机械化 剖析这些过程。我们还发现白细胞介素22（IL-22）是免疫系统的重要信号。 系统增强损伤后 ISC 介导的再生。为响应而开发的新初步数据 审稿人评论表明，我们的自身免疫模型反映了效应 T 细胞急性激活的 GVHD 胃肠道归巢分子的上调，活化的 T 细胞浸润胃肠道，并减少 IL-22治疗后的上皮损伤。 F-652是Generon公司开发的一种新型rhIL-22二聚体，具有 促进体内 ISC 恢复和上皮再生的转化潜力。额外的新数据 证明我们的 3D 成像方法可以量化 ISC 的损失、ISC 的特定入侵 区室和 GVHD 中血管整合素配体的定位。新的机械数据表明 MAdCAM-1 阻断特异性抑制 T 细胞隐窝侵袭并保护 ISC，表明该途径是 是 ISC 损伤的重要调节因子，而不仅仅是整个肠道迁移的调节因子。 我们将测试以下假设：1) T 细胞募集至 ISC 区室、ISC 耗尽以及 ISC 丢失 它们的再生能力是胃肠道中免疫介导的上皮损伤的共同特征，2) IL- 22给药可以保护ISC并促进损伤后的再生。 ISC 功能和消耗将 通过自身反应和同种反应实验方法进行评估，利用体内小鼠模型 系统性自身免疫和 GVHD 以及小鼠和人类肠道类器官的离体培养 与 UMC Utrecht、他们的类器官生物库以及先进的 ISC 专业知识合作。 IL-22治疗将 被评估为促进 ISC 功能的上皮靶向再生免疫疗法。不存在治疗方法 目前正在加速胃肠道从免疫病理学中恢复。该项目将导致机械化 了解 ISC 区室和免疫系统之间的基本相互作用，开启了 通过保护 ISC 和增强再生来治疗炎症性胃肠道疾病的新方向。