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.

目前对移植接受者如何从组织损害中恢复过的移植者几乎没有理解 移植物与宿主疾病（GVHD）和移植前调节。此外，几乎所有可用的策略 为了减少临床GVHD，以限制供体免疫系统以牺牲治疗移植vs为代价来做到这一点。 白血病/淋巴瘤（GVL）反应。 IL-22是最近表征的细胞因子，已显示为 在实验性炎症性肠病期间保护肠上皮。 IL-22受体表达是 仅限于非山摩托细胞，因此为移植中的受体上皮提供了特异性 环境。因此，对这种细胞因子的操纵可以保护移植受者中的上皮组织 改变供体免疫力或减少GVL。 我们的初步数据表明，IL-22是通过辐射式宿主衍生的移植后产生的 先天淋巴样细胞。在GVHD期间消除了这些细胞，宿主衍生的IL-22的缺乏导致 GVHD发病率，死亡率和病理增加。我们的数据还表明，IL-22在 GVHD用于维持从组织损伤中恢复上皮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。 我们建议测试IL-22促进上皮细胞生存和愈合的假设 在骨髓移植期间。该项目旨在研究在 - 移植，IL-22在减少GVHD和与条件相关的上皮损伤中的功能，以及 施用IL-22以降低移植后发病率和死亡率。我们的最终目标是发展 GVHD预防和治疗的新型治疗策略。潜在的治疗策略将是 在含白血病的小鼠中测试，以确保保留GVL活性。这些翻译研究将领导 更好地了解免疫生物学，肠道干细胞生理和上皮再生以及 还将导致减少移植后上皮损害的新策略。 相关性（请参阅说明）： 骨髓移植（BMT）是许多血液疾病的潜在治疗方法，但它是 受组织损伤和移植与宿主疾病（GVHD）的并发症的限制。该赠款旨在研究如何 IL-22保护移植受者免受GVHD和组织损害的侵害，该赠款旨在将其翻译 发现新治疗方法以改善BMT患者的健康和存活。