Regulation of the intestinal stem cell compartment after hematopoietic transplantation

造血移植后肠道干细胞区室的调节

• 批准号: 8911079
• 负责人: Alan M Hanash
• 金额: $ 55.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911079
• 关键词: Acute; Acute Graft Versus Host Disease; Address; Allogenic; Benign; Biological Models; Bone Marrow Transplantation; Caring; Cell Count; Cell Lineage; Cell physiology; Clinical; Clinical Trials; Complication; Cytokine Signaling; Data; Development; Disease; Environment; Epithelial; Epithelium; Experimental Models; Frequencies; Functional disorder; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Growth; Healed; Health; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Histologic; Human; Immune; Immune system; Immunity; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Impaired wound healing; In Vitro; Inflammatory; Injury; Intestinal Graft Versus Host Disease; Intestines; Kinetics; Large Intestine; Lead; Maintenance; Malignant - descriptor; Measures; Mediating; Memorial Sloan-Kettering Cancer Center; Modeling; Morbidity - disease rate; Mus; Natural regeneration; Organoids; Paneth Cells; Pathology; Pattern; Positioning Attribute; Radiation Injuries; Reaction; Recombinant Interleukins; Recombinants; Recovery; Regulation; Reporter; Research; Resources; Role; Signal Transduction; Small Intestines; Stem cells; Steroids; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Transplant Recipients; Transplantation; Work; cell injury; conditioning; cytokine; dimer; gastrointestinal; graft vs host disease; graft vs leukemia effect; healing; immune function; improved; in vitro testing; in vivo; in vivo Model; interleukin-22; intestinal crypt; intestinal epithelium; leukemia/lymphoma; mortality; novel; novel strategies; programs; public health relevance; receptor; reconstitution; regenerative; response; stem cell biology; stem cell niche; success; tissue regeneration

 DESCRIPTION (provided by applicant): Damage to the gastrointestinal (Gl) tract is a frequent complication of hematopoietic stem cell/bone marrow transplantation (BMT). This therapy-related toxicity may be due to pre-transplant conditioning or T cell-mediated graft vs. host disease (GVHD), and current immunosuppressive treatments for GI GVHD are inadequate. The contribution of intestinal stem cell (ISC) damage to GVHD pathophysiology and the role of the immune system in mediating damage to the ISC compartment are poorly understood. Experimental models of acute GI GVHD closely recapitulate the immunologic pathophysiology of the clinical disease, providing an opportunity to investigate the relationship between injury to ISCs vs. injury to the ISC niche in the resulting intestinal pathology. This project brings togethe a multi-disciplinary team with expertise in mucosal immunology, GI damage from GVHD and radiation injury, ISC biology, and cytokine signaling to develop a comprehensive understanding of how BMT and GVHD can influence the ISC compartment and lead to intestinal damage. Our preliminary data demonstrate that both ISCs and the Paneth cells constituting the stem cell niche are depleted in experimental GVHD. Additionally, ISCs were found to express the receptor for Interleukin-22 (IL-22). Signaling of IL-22 within the intestines has recently been shown to limit pathology in wounded epithelium. We found that in vivo administration of IL-22 to mice post-BMT reduced GVHD-related intestinal pathology and limited the loss of ISCs due to GVHD. We also found that ex vivo intestinal crypt culture with IL-22 led to increased growth of intestinal organoids and ISC regeneration. Finally, organoid growth was also enhanced by F-652, a recombinant human IL-22 dimer, and treatment of transplanted mice with F-652 led to reduced systemic signs of GVHD and significantly reduced GVHD mortality. We propose to test the hypothesis that the loss of ISCs after BMT is due to both conditioning-related and immune-mediated damage to the ISC compartment, and we hypothesize that the benefit of IL-22 in epithelial regeneration is due to direct stimulation of ISCs. ISC function and ISC depletion will b evaluated in experimental BMT models, utilizing both in vivo models of GVHD and ex vivo culture of intestinal organoids. In addition, we will test the mechanisms by which IL-22 can protect the ISC compartment from injury. Treatment with IL-22 post-BMT will thus be evaluated as an epithelial-focused regenerative immunotherapy to reduce transplant-related morbidity and mortality by promoting ISC function. No current therapy exists to accelerate tissue recovery from GVHD, but such a strategy, potentially with F-652, could work in a complimentary fashion with immunosuppressive approaches to treat GVHD and reduce tissue damage. This project will lead to a better understanding of the interactions between the ISC compartment and the immune system, opening a new direction for treatment of inflammatory GI disease by augmenting tissue regeneration.

 描述（由申请人提供）：胃肠道（GI）损伤是造血干细胞/骨髓移植（BMT）的常见并发症，这种与治疗相关的毒性可能是由于移植前调理或T细胞介导的移植物造成的。与宿主疾病（GVHD）相比，目前针对胃肠道 GVHD 的免疫抑制治疗不足 肠道干细胞（ISC）损伤对 GVHD 的影响。病理生理学和免疫系统在介导 ISC 区室损伤中的作用知之甚少。急性 GI GVHD 的实验模型密切概括了临床疾病的免疫病理生理学，为研究损伤与 ISC 区室之间的关系提供了机会。 ISC 与由此产生的肠道病理学中 ISC 生态位的损伤该项目汇集了一个多学科团队，他们在粘膜免疫学、GVHD 和放射损伤引起的胃肠道损伤、ISC 生物学和细胞因子信号转导方面具有专业知识，以全面了解如何进行治疗。 BMT 和 GVHD 可以影响 ISC 区室并导致肠道损伤。此外，实验性 GVHD 中构成干细胞生态位的 ISC 和潘氏细胞均被耗尽。最近发现 ISC 表达肠内白细胞介素 22 (IL-22) 的受体，这可以限制受伤上皮细胞的病理学变化。 BMT 减少了 GVHD 相关的肠道病理，并限制了 GVHD 导致的 ISC 损失。我们还发现，用 IL-22 进行离体肠隐窝培养会导致肠道类器官和 ISC 的生长增加。最后，F-652（一种重组人 IL-22 二聚体）也增强了类器官的生长，并且用 F-652 治疗移植小鼠可显着减少 GVHD 的全身症状并降低 GVHD 死亡率。 BMT 后 ISC 的损失是由于对 ISC 区室的调理相关和免疫介导的损伤造成的，我们发现 IL-22 在上皮再生中的益处是由于直接刺激ISC 功能和 ISC 消耗将在实验性 BMT 模型中进行评估，利用 GVHD 的体内模型和肠道类器官的离体培养。此外，我们将测试 IL-22 保护 ISC 区室免受损伤的机制。因此，BMT 后使用 IL-22 的治疗将被评估为一种以上皮为中心的再生免疫疗法，通过促进 ISC 功能来降低移植相关的发病率和死亡率。目前尚不存在加速组织恢复的疗法。 GVHD，但这样的策略（可能与 F-652 一起）可以与免疫抑制方法以互补的方式发挥作用，以治疗 GVHD 并减少组织损伤。该项目将有助于更好地了解 ISC 区室和免疫系统之间的相互作用。通过增强组织再生开辟了治疗炎症性胃肠道疾病的新方向。