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（由申请人提供）：同种异体造血移植是一种治疗治疗的治疗方法，可用于许多原本无法治愈的恶性和非恶性HE-马托波氏症。尽管进行了数十年的深入研究，但仍然存在几种重大并发症，包括长时间移植后免疫缺乏和移植物与宿主病（GVHD）。胃肠道GVHD尤其是急性GVHD相关死亡率的主要因素，而对其他靶器官（例如胸腺）（例如胸腺）的大坝对移植后免疫缺陷产生了重大贡献。尽管在理解供体移植者对移植受者的免疫反应方面取得了很多进展，但对移植受者如何对GVHD的反应及其伴随损害的理解很少。此外，几乎所有可用于减少临床GVHD的策略通过以治疗性移植与白血病/淋巴瘤（GVL）反应为代价来限制供体免疫系统。 IL-22是最近特征的细胞因子，已显示可在实验性炎症性肠病期间保护肠上皮。 IL-22受体表达仅限于非山地肌细胞，因此在移植设置中为受体上皮提供了特异性。因此，对这种细胞因子的操纵可以在不改变供体免疫力或还原GVL的情况下保护移植受体中的上皮组织。我们的初步数据表明，IL-22是通过抗射击宿主的先天淋巴样细胞产生移植后的。如果宿主衍生的IL-22导致GVHD发病率，死亡率和病理学增加，则在GVHD和缺乏症中消除了这些细胞。我们的数据还表明，北部上皮维持所需的肠道干细胞（ISC）是GVHD的靶标，并且IL-22对于在GVHD期间保护这些ISC可能至关重要。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给药可以消除由于GVHD而导致的百里香损伤。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生存和愈合。该项目的目的是：研究IL-22缺乏对实验模型中GVHD和与条件相关的上皮损伤的影响，以及研究IL-22对降低移植物后发病率和死亡率的影响。我们的最终目标是制定一种新型的治疗策略，以预防和治疗GVHD。潜在的治疗策略将在含白血病的小鼠中进行测试，以确保保留GVL活性。我们预计这些翻译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，但也将导致发展新的策略，以减少移植后上皮损害并改善具有恶性和非恶性血肿的移植患者的生活。具体目的是：1：研究IL-22缺乏对GVHD的影响，与条件相关的损伤和移植后免疫功能。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：研究施用IL-22，以减少移植后组织损伤和移植后免疫的增强。我们将使用全身短作用重组IL-22治疗移植受者，诱导具有工程表达载体的本构IL-22，并用中间尿液IL-22-加载的纳米颗粒施用IL-22来测试治疗策略。申请人艾伦·汉纳什（Alan Hanash）博士是纪念斯隆 - 凯特林癌症中心（MSKCC）的医学肿瘤学研究员，概述了一项为期五年的职业计划，该计划将以他的免疫学和临床肿瘤学/恶性血液学的背景为基础。在Marcel van den Brink博士的指导下。 Hanash博士将由该领域的国际认可专家咨询委员会指导。最后，鉴于其在丰富且协作的环境中培训医师科学家的杰出记录，该计划是在MSKCC的医学与计划部门的医学和计划部门中执行的。在K08奖提供的支持下，Hanash博士的项目将导致对淋巴样细胞与基质维护之间关系的新型生物学见解，以及在炎症组织损害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通过自己的实验室和R01资金来帮助汉纳什（Hanash）过渡到独立调查员。