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: 8680364
• 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/8680364
• 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.

描述(申请人提供)：异基因造血移植是一种对许多恶性和非恶性造血疾病的根治疗法，否则这些疾病是无法治愈的。尽管进行了数十年的密集研究，但仍有几个主要并发症，包括移植后长期免疫缺陷和移植物抗宿主病(GVHD)。尤其是胃肠道移植物抗宿主病是导致急性移植物抗宿主病相关死亡的主要因素，而对其他靶器官如胸腺的损伤也是造成移植后免疫缺陷的重要原因。虽然在了解供者移植物对移植受者的免疫反应方面取得了很大进展，但对移植受者如何应对GVHD及其伴随的损害仍知之甚少。此外，几乎所有可用来减少临床GVHD的策略都是通过限制供者免疫系统来实现的，代价是治疗性移植物对白血病/淋巴瘤(GVL)的反应。IL-22是一种新近鉴定的细胞因子，在实验性炎症性肠病过程中具有保护肠道上皮的作用。IL-22受体的表达仅限于非造血细胞，因此为移植环境中的受体上皮提供了特异性。因此，操纵这种细胞因子可以在不改变供者免疫或降低GVL的情况下保护移植受者的上皮组织。我们的初步数据表明，IL-22是移植后由抗辐射宿主来源的先天淋巴样细胞产生的。这些细胞在GVHD期间被消除，如果宿主来源的IL-22导致GVHD发病率、死亡率和病理学增加，则缺乏这些细胞。我们的数据还表明，正常上皮维持所需的肠道干细胞(ISC)是GVHD的靶点，而IL-22可能在GVHD期间对这些ISC的保护起关键作用。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，应用IL-22可以消除移植物抗宿主病引起的百里香损伤。我们建议测试假设，IL-22促进存活和修复受损的上皮在ALLOW非专利移植。本课题旨在：在实验模型上研究IL-22缺乏对移植物抗宿主病(GVHD)和调节相关的上皮损伤的影响，并研究IL-22对降低移植后发病率和死亡率的作用。我们的最终目标是开发一种预防和治疗移植物抗宿主病的新的治疗策略。潜在的治疗策略将在携带白血病的小鼠身上进行测试，以确保GVL的活性得到保存。我们预计，这些翻译研究不仅将有助于更好地了解免疫生物学、肠道 干细胞生理学、上皮再生和移植物抗宿主病病理生理学，但也将导致开发新的策略，以减少移植后的上皮损伤，并改善患有恶性和非恶性血液系统疾病的移植患者的生活。具体目的为：1.研究IL-22缺乏对移植物抗宿主病(GVHD)、条件性损伤及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。2.研究IL-22在减轻移植后组织损伤、增强移植后免疫功能方面的作用。我们将用系统性短效重组IL-22治疗移植受者，用工程表达载体诱导结构性IL-22，并用中程IL-22载药纳米粒给药，以测试治疗给药策略。申请者艾伦·哈纳什博士是纪念斯隆-凯特琳癌症中心(MSKCC)的肿瘤学研究员，他概述了一份为期五年的职业计划，该计划将建立在他在免疫学和临床肿瘤学/恶性血液学背景的基础上。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博士将利用体内翻译临床前模型，结合遗传缺陷和细胞因子管理方法，研究IL-22在减少同种异体移植后组织损伤和增强免疫功能方面的作用。哈纳什博士将接受该领域国际公认专家组成的咨询委员会的指导。最后，鉴于MSKCC在丰富和协作的环境中培训医生-科学家的杰出记录，该计划在MSKCC的医学部和免疫学计划中执行是理想的。在K08奖项的支持下，Hanash博士的项目将导致对淋巴样细胞和间质维护之间的关系的新的生物学见解的发展，以及在炎症组织损伤期间促进这种维护的临床有效策略。此外，该项目的职业发展目标是帮助Hanash博士转型为拥有自己的实验室和R01资金的独立研究员。