IL-22 in epithelial regeneration after allogeneic transplant

IL-22在同种异体移植后上皮再生中的作用

• 批准号: 8354485
• 负责人: Alan M Hanash
• 金额: $ 13.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354485
• 关键词: Acute; Acute Graft Versus Host Disease; Advisory Committees; Age; Aging; Allogenic; Autoimmunity; Award; Benign; Biological Models; Biology; CD4 Positive T Lymphocytes; Celiac Disease; Cell physiology; Cells; Clinical; Clinical Oncology; Combined Modality Therapy; Data; Development; Disease; Engineering; Ensure; Environment; Epithelial; Epithelium; Experimental Models; Functional disorder; Funding; Generations; Generic Drugs; Genetic; Goals; Grant; Healed; Helper-Inducer T-Lymphocyte; Hematological Disease; Hematology; Hematopoietic; Homologous Transplantation; Immune; Immune response; Immune system; Immunity; Immunobiology; Immunology; Immunosuppression; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Intestinal Graft Versus Host Disease; Intestines; Laboratories; Lead; Lymphoid Cell; Lymphoma; Maintenance; Malignant - descriptor; Medical Oncology; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Morbidity - disease rate; Mus; Natural regeneration; Non-Malignant; Organ; Pathology; Pathway interactions; Patients; Physicians; Play; Pre-Clinical Model; Prevention strategy; Quality of life; Radiation; Radio; Recombinant Interleukins; Research; Research Personnel; Resistance; Role; Scientist; Shock; Specificity; Stem cells; T-Lymphocyte; Tars; Techniques; Testing; Therapeutic; Thromboplastin; Thyme; Thymus Gland; Tissues; Toxic effect; Training; Translating; Translations; Transplant Recipients; Transplantation; Transplanted tissue; career; career development; chemotherapy; conditioning; cytokine; expression vector; gastrointestinal; graft vs host disease; graft vs leukemia effect; healing; immune function; improved; in vivo; insight; interleukin-21; interleukin-22; intestinal epithelium; leukemia; leukemia/lymphoma; mortality; nanoparticle; neutralizing antibody; novel; novel strategies; novel therapeutics; preclinical study; prevent; programs; receptor expression; reconstitution; response; stem; success; translational study

DESCRIPTION (provided by applicant): Allogeneic hematopoietic transplantation is a curative therapy for numerous malignant and non-malignant he- matopoietic diseases that are otherwise incurable. Despite decades of intensive research, several major complications remain, including prolonged post-transplant immune deficiency and graft vs. host disease (GVHD). Gastrointestinal GVHD in particular is the predominant contributor to acute GVHD-related mortality, and dam- age to other target organs such as the thymus contributes significantly towards post-transplant immune deficiency. While much progress has been made toward understanding the immune response of the donor graft against the transplant recipient, there is little understanding of how transplant recipients respond to GVHD and its concomitant damage. 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 of this cytokine could there- fore 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 radio resistant host-derived innate lymphoid cells. These cells were eliminated during GVHD and deficiency if host-derived IL-22 led to increased GVHD morbidity, mortality, and pathology. Our data also indicate that the intestinal stem cells (ISC) necessary for nor- mal epithelial maintenance are targets of GVHD, and that IL-22 may be critical for the protection of these ISC during GVHD. Finally, our data indicate that IL-22 is critical for protecting the function of thyme epithelium post-transplant, an that IL-22 administration can eliminate thyme damage due to GVHD. We propose to test the hypothesis that IL-22 promotes survival and healing of damaged epithelium during allow- generic transplant. This project aims to: study the effects of IL-22 deficiency on GVHD and conditioning-related epithelial damage in experimental models, and study 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. We anticipate that these translational studies will not only lead to better understanding of immunobiology, intestinal stem cell physiology, epithelial regeneration, and GVHD pathophysiology, but will also lead to the development novel strategies to reduce epithelial damage post-transplant and improve the lives of transplant patients with both malignant and non-malignant hematopoietic disease. The specific aims are: 1: To study the effects of IL-22 deficiency on GVHD, conditioning-related damage, and post-transplant immune function. We will utilize a combination of IL-22 KO mice and IL-22 neutralizing antibody to assess the role of IL- 22 in target tissues and cells. 2: To study administration of IL-22 for reduction of post-transplant tissue damage and augmentation of post- transplant immunity. We will treat transplants recipients with systemic short-acting recombinant IL-22, induce constitutive IL-22 with an engineered expression vector, and administer IL-22 with intermediate-duration IL-22- loaded nanoparticles to test therapeutic administration strategies. The applicant, Dr. Alan Hanash, a medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC) has outlined a five-year career plan that will build upon his background in immunology and clinical oncology/malignant hematology. Under the mentorship of Dr. Marcel van den Brink, a recognized leader in transplant immunology, GVHD, and immune reconstitution post-transplant, Dr. Hanash will utilize translational in vivo pre-clinical models with a combination of genetic deficiencies and cytokine administration approaches to study the role of IL-22 in reducing tissue damage and augmenting immune function after allogeneic transplant. Dr. Hanash will be mentored by an Advisory Committee of internationally recognized experts in the field. Finally, this plan is ideally carried out in the Department of Medicine and Program in Immunology at MSKCC, given its distinguished record for training physician-scientists in a rich and collaborative environment. With the support provided by the K08 award, Dr. Hanash's project will lead to the development of novel biologic insights into the relationship between lymphoid cells and stromal maintenance, as well as clinically effective strategies for promoting this maintenance during inflammatory tissue damage. In addition, the career development goal of this project is to help Dr. Hanash transition into an independent investigator with his own laboratory and R01 funding. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic transplantation is a potentially curative treatment for benign and malignant hematologic diseases, however the success of transplantation is limited by complications of graft vs. host-disease and complications of the immunosuppression meant to prevent it. Our preliminary data indicates that IL-22 is a protective factor for the tissues of transplant recipients, and administration of IL-22 may prevent the tissue damage associated with graft vs. host disease without limiting the critical functions of the donor immune sys- tem. This grant aims to study the mechanisms by which IL-22 may reduce tissue damage in transplant recipients and translate these findings into therapeutic strategies that will improve the survival and quality of life for patients undergoing allogeneic transplantation.

描述（由申请人提供）：同种异体造血移植是许多无法治愈的恶性和非恶性造血疾病的治疗方法。尽管经过数十年的深入研究，一些主要并发症仍然存在，包括长期移植后免疫缺陷和移植物抗宿主病（GVHD）。特别是胃肠道 GVHD 是急性 GVHD 相关死亡的主要原因，而胸腺等其他靶器官的损伤则显着导致移植后免疫缺陷。虽然在了解供体移植物对移植受者的免疫反应方面已经取得了很大进展，但对于移植受者如何应对 GVHD 及其伴随的损害却知之甚少。此外，几乎所有可用于减少临床 GVHD 的策略都是通过限制供体免疫系统来实现的，但以牺牲治疗性移植物抗白血病/淋巴瘤 (GVL) 反应为代价。 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 受体表达仅限于非造血细胞，从而为移植环境中的受体上皮提供特异性。因此，操纵这种细胞因子可以保护移植受者的上皮组织，而不改变供体免疫或降低 GVL。我们的初步数据表明，IL-22 是由抗辐射宿主来源的先天淋巴细胞在移植后产生的。如果宿主来源的 IL-22 导致 GVHD 发病率、死亡率和病理学增加，则这些细胞在 GVHD 期间被消除。我们的数据还表明，正常上皮维持所需的肠干细胞（ISC）是 GVHD 的靶点，而 IL-22 可能对于 GVHD 期间保护这些 ISC 至关重要。最后，我们的数据表明，IL-22 对于保护移植后百里香上皮的功能至关重要，IL-22 给药可以消除 GVHD 引起的百里香损伤。我们建议检验以下假设：IL-22 在允许通用移植期间促进受损上皮的存活和愈合。该项目的目的是：在实验模型中研究 IL-22 缺乏对 GVHD 和条件相关上皮损伤的影响，并研究使用 IL-22 来降低移植后发病率和死亡率。我们的最终目标是开发一种新的治疗策略来预防和治疗 GVHD。潜在的治疗策略将在患有白血病的小鼠中进行测试，以确保 GVL 活性得到保留。我们预计这些转化研究不仅会更好地理解免疫生物学、肠道 干细胞生理学、上皮再生和 GVHD 病理生理学，但也将导致开发新策略，以减少移植后上皮损伤并改善患有恶性和非恶性造血疾病的移植患者的生活。具体目标是： 1：研究IL-22缺乏对GVHD、调理相关损伤和移植后免疫功能的影响。我们将利用IL-22 KO小鼠和IL-22中和抗体的组合来评估IL-22在靶组织和细胞中的作用。图2：研究施用IL-22以减少移植后组织损伤并增强移植后免疫力。我们将用全身性短效重组IL-22治疗移植受者，用工程化表达载体诱导组成型IL-22，并用负载IL-22的中等持续时间的纳米颗粒施用IL-22以测试治疗施用策略。申请人是纪念斯隆-凯特琳癌症中心 (MSKCC) 的肿瘤内科研究员艾伦·哈纳什 (Alan Hanash) 博士，他概述了一个五年职业计划，该计划将以他在免疫学和临床肿瘤学/恶性血液学方面的背景为基础。在移植免疫学、GVHD 和移植后免疫重建领域公认的领导者 Marcel van den Brink 博士的指导下，Hanash 博士将利用转化体内临床前模型，结合遗传缺陷和细胞因子施用方法来研究 IL-22 在同种异体移植后减少组织损伤和增强免疫功能中的作用。哈纳什博士将接受由该领域国际知名专家组成的咨询委员会的指导。最后，鉴于 MSKCC 在丰富的协作环境中培训医师科学家的杰出记录，该计划非常适合在 MSKCC 的医学系和免疫学项目中实施。在 K08 奖的支持下，Hanash 博士的项目将促进对淋巴细胞和基质维持之间关系的新生物学见解的发展，以及在炎症组织损伤期间促进这种维持的临床有效策略。此外，该项目的职业发展目标是帮助Hanash博士转型为一名拥有自己的实验室和R01资助的独立研究者。 公共卫生相关性：同种异体造血移植是治疗良性和恶性血液疾病的一种潜在治疗方法，但移植的成功受到移植物抗宿主疾病并发症和旨在预防移植物抗宿主疾病并发症的限制。我们的初步数据表明，IL-22 是移植受者组织的保护因子，施用 IL-22 可能会阻止组织 与移植物抗宿主病相关的损伤，而不限制供体免疫系统的关键功能。这笔赠款旨在研究 IL-22 减少移植受者组织损伤的机制，并将这些发现转化为治疗策略，以提高接受同种异体移植的患者的生存率和生活质量。