IL-22 and Mucosal Immunity During Bone Marrow Transplantation

骨髓移植过程中 IL-22 和粘膜免疫

• 批准号: 9277365
• 负责人: Marcel R M van den Brink
• 金额: $ 37.87万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277365
• 关键词: Acute; Address; Adult; Aging; Allogenic; Allografting; Autoimmunity; Bone Marrow Transplantation; Celiac Disease; Cell Compartmentation; Cell Transplantation; Cell physiology; Cells; Clinical; Data; Development; Disease; Disease Management; Effector Cell; Engineering; Ensure; Epithelial; Epithelium; Gastrointestinal tract structure; Goals; Grant; Health; Hematological Disease; Hematopoietic stem cells; Immune; Immune system; Immunity; Immunobiology; Immunologics; Individual; Infection; Inflammatory Bowel Diseases; Institution; Instruction; Intestines; Knockout Mice; Lead; Lymphoid Cell; Maintenance; Marrow; Morbidity - disease rate; Mucosal Immunity; Mus; Natural regeneration; Pathology; Pathway interactions; Patients; Play; Population; Prevention approach; Prevention strategy; Radiation; Recovery; Regulation; Role; Sampling; Signal Transduction; Source; Specificity; Stem cells; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; Transplanted tissue; Umbilical cord structure; antimicrobial; aryl hydrocarbon receptor ligand; chemotherapy; conditioning; cost; curative treatments; cytokine; expression vector; gastrointestinal; gastrointestinal epithelium; healing; immune function; improved; interleukin-22; interleukin-23; intestinal epithelium; leukemia; leukemia/lymphoma; microbial; mortality; nanoparticle; neutralizing antibody; novel; novel strategies; novel therapeutics; preclinical study; programs; radioresistant; receptor expression; reconstitution; response; translational study; virtual

There is currently little understanding of how transplant recipients recover from tissue damage due to graft vs. host disease (GVHD) and pre-transplant conditioning. Furthermore, virtually all strategies available to reduce clinical GVHD do so by limiting the donor immune system at the expense of therapeutic graft vs. leukemia/lymphoma (GVL) responses. iL-22 is a recently characterized cytokine that has been shown to protect intestinal epithelium during experimental inflammatory bowel disease. IL-22 receptor expression is restricted to non-hematopoietic cells, thus providing specificity to recipient epithelium in the transplant setting. Manipulation ofthis cytokine could therefore protect epithelial tissues in transplant recipients without altering donor immunity or reducing GVL. Our preliminary data demonstrate that IL-22 is produced post-transplant by radioresistant host-derived innate lymphoid cells. These cells were eliminated during GVHD, and deficiency of host-derived IL-22 led to increased GVHD morbidity, mortality, and pathology. Our data also indicate that iL-22 may be critical during GVHD for maintaining the intestinal stem cells necessary for epithelial recovery from tissue damage. Finally, our data indicate that IL-22 is essential for protecting the function of thymic epithelium post-transplant, and that IL-22 administration can eliminate thymic damage due to GVHD. We propose to test the hypothesis that IL-22 promotes survival and healing of damaged epithelium during bone marrow transplantation. This project aims to study the regulation of IL-22 expression post- transplant, the function of IL-22 in reducing GVHD and conditioning-related epithelial damage, and the administration of IL-22 for reduction of post-transplant morbidity and mortality. Our ultimate goal is to develop a novel therapeutic strategy for prevention and treatment of GVHD. Potential therapeutic strategies will be tested in leukemia-bearing mice to ensure that GVL activity is preserved. These translational studies will lead to better understanding of immunobiology, intestinal stem cell physiology, and epithelial regeneration, and will also lead to novel strategies for reducing epithelial damage post-transplant. RELEVANCE (See instructions): Bone marrow transplantation (BMT) is a potentially curative treatment for many blood diseases, but it is limited by complications of tissue damage and graft vs. host disease (GVHD). This grant aims to study how IL-22 protects transplant recipients from GVHD and tissue damage, and this grant aims to translate these findings into new treatments to improve the health and survival of BMT patients.

目前，人们对移植受者如何从因移植引起的组织损伤中恢复知之甚少。 移植物抗宿主病（GVHD）和移植前调理。此外，几乎所有可用的策略 为了减少临床 GVHD，可以通过限制供体免疫系统来减少治疗性移植物与非移植物之间的差异。 白血病/淋巴瘤（GVL）反应。 iL-22 是一种最近被鉴定的细胞因子，已被证明可以 在实验性炎症性肠病期间保护肠上皮。 IL-22 受体表达为 仅限于非造血细胞，从而为移植物中的受体上皮提供特异性 环境。因此，操纵这种细胞因子可以保护移植受者的上皮组织，而无需 改变供体免疫力或降低 GVL。 我们的初步数据表明，IL-22 是由抗辐射宿主来源的移植后产生的。 先天淋巴细胞。这些细胞在 GVHD 期间被消除，宿主来源的 IL-22 的缺乏导致 GVHD 发病率、死亡率和病理学增加。我们的数据还表明 iL-22 在 GVHD 用于维持上皮细胞从组织损伤中恢复所需的肠道干细胞。最后， 我们的数据表明 IL-22 对于保护移植后胸腺上皮的功能至关重要，并且 IL-22 给药可以消除 GVHD 引起的胸腺损伤。 我们建议检验 IL-22 促进受损上皮存活和愈合的假设 骨髓移植期间。本项目旨在研究IL-22表达后的调控。 移植、IL-22 在减少 GVHD 和调理相关的上皮损伤中的功能，以及 施用 IL-22 可降低移植后发病率和死亡率。我们的最终目标是发展 预防和治疗 GVHD 的新治疗策略。潜在的治疗策略将是 在患有白血病的小鼠中进行测试，以确保 GVL 活性得到保留。这些转化研究将引领 更好地了解免疫生物学、肠道干细胞生理学和上皮再生，以及 还将带来减少移植后上皮损伤的新策略。 相关性（参见说明）： 骨髓移植 (BMT) 是治疗许多血液疾病的一种潜在疗法，但它 受到组织损伤和移植物抗宿主病（GVHD）并发症的限制。这笔赠款旨在研究如何 IL-22 保护移植受者免受 GVHD 和组织损伤，这笔赠款旨在转化这些 改善 BMT 患者健康和生存的新疗法的发现。