IL-22 in epithelial regeneration after allogeneic transplant

描述（由申请人提供）：同种异体造血移植是许多恶性和非恶性造血疾病的根治性治疗方法，否则无法治愈。尽管数十年的深入研究，几个主要的并发症仍然存在，包括移植后长期免疫缺陷和移植物抗宿主病（GVHD）。特别是胃肠道GVHD是导致急性GVHD相关死亡的主要原因，而对其他靶器官（如胸腺）的阻碍也显著导致移植后免疫缺陷。虽然在了解供体移植物对移植受体的免疫反应方面取得了很大进展，但对移植受体如何对GVHD及其伴随的损害作出反应知之甚少。此外，几乎所有可用于减少临床GVHD的策略都是以牺牲移植物对白血病/淋巴瘤（GVL）的治疗性反应为代价来限制供体免疫系统。IL-22是一种新发现的细胞因子，已被证明在实验性炎症性肠病中保护肠上皮。IL-22受体的表达仅限于非造血细胞，因此在移植环境中对受体上皮具有特异性。因此，操纵这种细胞因子可以保护移植受者的上皮组织，而不会改变供体免疫或降低GVL。我们的初步数据表明，IL-22是在移植后由宿主产生的抗放射性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缺乏导致GVHD发病率，死亡率和病理增加。我们的数据还表明，正常上皮维持所必需的肠干细胞（ISC）是GVHD的靶点，IL-22可能对GVHD期间这些ISC的保护至关重要。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，并且IL-22可以消除GVHD引起的百里香损伤。我们提出验证IL-22在移植过程中促进受损上皮存活和愈合的假设。本项目旨在：通过实验模型研究IL-22缺乏对GVHD和调节性相关上皮损伤的影响，研究IL-22对降低移植后发病率和死亡率的影响。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白血病小鼠中进行测试，以确保GVL活性得以保留。我们期望这些转化研究不仅将导致更好地理解免疫生物学，肠

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.