Investigating the role of interleukin-22 in thymus function

研究 IL-22 在胸腺功能中的作用

基本信息

批准号：
9189154
负责人：
Jarrod Dudakov
金额：
$ 24.9万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189154
关键词：
Adrenal Cortex Hormones Age Aging Allogenic Animals Area Atrophic Autoimmune Diseases CD8B1 gene Cancer Patient Cell Differentiation process Cell physiology Cells Cellularity Chronic Clinical Communicable Diseases Competence Dendritic Cells Epithelial Epithelial Cell Proliferation Epithelial Cells Event Genetic Goals HIV Health Hematopoietic Stem Cell Transplantation Hepatitis B Homeostasis Immune Immune system Immunity Individual Infection Injury Intestines Kinetics Lead Lung Lymphoid Lymphoid Cell Maintenance Malignant - descriptor Mediating Mentors Molecular Morbidity - disease rate Mus Mutant Strains Mice Natural Immunity Natural regeneration Nuclear Accidents Pathway interactions Phase Physiology Process Production Radiation Injuries Radiation therapy Radio Recombinant Interleukins Recovery Rejuvenation Relapse Resistance Risk Role Shock Signal Transduction Skin Stem cells Stimulus T-Cell Development T-Lymphocyte Terrorism Thymic epithelial cell Thymocyte Development Thymus Gland Translating Translations Transplantation Up-Regulation Whole-Body Irradiation Work age related antimicrobial arm base cancer therapy chemotherapy clinically relevant conditioning cytokine experience graft vs host disease improved innovation interleukin-22 interleukin-23 mortality novel preclinical study reconstitution regenerative repaired thymocyte

项目摘要

DESCRIPTION (provided by applicant): Endogenous regeneration of the thymus is a crucial function that allows for renewal of immune competence following infection, shock or common cancer therapies such as cytoreductive chemo- or radiation therapy. Thymic regenerative capacity diminishes with age and remains a poorly understood area. This is particularly relevant for recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), who experience prolonged post-transplant T cell deficiency caused by cytoreductive conditioning and graft-versus- host disease (GVHD), which results in increased morbidity and mortality from infections and malignant relapse. Therefore, the main goal of this proposal is to understand the proceses underlying endogenous thymic regeneration so that they may be exploited into clinically relevant strategies for immune rejuvenation. Interleukin-22 (IL-22) is a recently described cytokine that is produced by T-helper (Th)-17 cells and innate lymphoid cells (ILCs) and promotes innate immunity and homeostasis of epithelial cells in the intestines, lung and skin. We have recently revealed a network of thymic regeneration centred on IL-22 and triggered by the depletion of CD4+CD8+ double positive (DP) developing thymocytes. Although at baseline IL-22 deficiency was redundant for normal thymopoiesis, thymic recovery was impaired in IL-22-deficient mice and intrathymic levels of IL-22 were significantly increased in wildtype mice following thymic injury. IL-22, which signalled through thymic epithelial cells (TECs) and promoted their proliferation and survival, was upregulated by radio- resistant innate lymphoid cells (ILCs) after thymic injury in an IL-23 dependent manner. Importantly, administration of recombinant IL-22 enhanced repair folowing thymic injury. These findings highlight an endogenous network of thymus regeneration whereby 1) the depletion of DP thymocytes triggers 2) upregulation of IL-23 by DCs, which induces 3) the production of IL-22 by thymic ILCs. This cascade of events leads to regeneration of the supporting epithelial microenvironment and, ultimately, to rejuvenation of thymopoiesis. Based on these findings, we hypothesize that (a) IL-22-mediated regeneration will be translated into functionally enhanced T cell reconstitution, (b) endogenous regenerative pathways in the thymus are triggered by a damage-sensing mechanism intrinsically tied to the loss of DP thymocytes and a negative signal they typically produce, (c) I-22 directly promotes the proliferation of TECs but also enhances their capacity to respond to additional trophic factors, and (d) breakdown of IL-22 regenerative pathways underlie chronic thymic involution, including age-related atrophy. Exploring the functional translation of IL-22-mediated regeneration is a natural progression of my postdoctoral work and will constitute the K99 mentored phase of this proposal. A logical extension of these studies, exploring the underlying mechanisms and implications of the IL-22 regenerative pathway, will be explored in the independent R00 phase of this proposal. The mechanistic and pre-clinical studies outlined in this proposal have the potential to define an important novel pathway in thymic regeneration, which could result in clinical approaches to enhance T cell immunity, not only for recipients of allo-HSCT, but also for individuals with T cell deficiencies due to aging (lymphoid atrophy), autoimmune diseases, genetic causes (such as SCID), infectious diseases (HIV, hepatitis B/C), corticosteroids, shock, radio- or chemo-therapy and radiation injury (nuclear accident or terrorism).

描述（由申请人提供）：胸腺的内源性再生是一种关键功能，可在感染，休克或常见的癌症治疗（例如细胞减少化学疗法或放射疗法）后更新免疫能力。胸腺再生能力随着年龄的增长而降低，并且仍然是一个鲜为人知的领域。这与同种异性造血干细胞移植（Allo-HSCT）的接受者尤其重要，后者经历了由细胞减少调节性调节和接枝抗疾病（GVHD）引起的长时间移植后T细胞缺乏症（GVHD），从而导致了产生和恶性疾病的发病率增加。因此，该提案的主要目的是了解内源性胸腺再生的基础进程，以便可以将它们利用为临床上相关的免疫复兴策略。白介素-22（IL-22）是最近描述的细胞因子，由T-甘油（Th）-17细胞和先天淋巴样细胞（ILC）产生，并促进肠道，肺和皮肤中上皮细胞的先天免疫和稳态。我们最近揭示了以IL-22为中心的胸腺再生网络，并由CD4+ CD8+ Double Double（DP）开发胸腺细胞的耗竭触发。尽管在基线IL-22下缺乏率对于正常的胸腺胞菌是冗余，但在IL-22缺陷型小鼠中胸膜恢复受损，胸腺损伤后野生型小鼠的IL-22的胸膜胸膜水平显着增加。 IL-22通过胸腺上皮细胞（TEC）发出信号并促进其增殖和存活，在胸腺损伤后以IL-23依赖性的方式上调了抗射膜的先天淋巴样细胞（ILC）。重要的是，施用重组IL-22增强了胸膜损伤的修复。这些发现突出了胸腺再生的内源性网络，其中1）DP胸腺细胞的耗竭触发2）DCS上的IL-23上调，DC诱导3）胸腺ILC的IL-22产生。这种级联的事件导致支持上皮微环境的再生，并最终导致胸腺无索的恢复活力。基于这些发现，我们假设（a）IL-22介导的再生将被翻译成功能增强的T细胞重建，（b）胸腺内源性再生途径是由损害感应机制本质上触发的，这与dpymocys intermistion the the the the the the the the the the the the the-22 i-22 i-22 the the the thailsements thements thements thements thements thementy触发。为了应对其他营养因子，以及（d）IL-22再生途径的分解是慢性胸腺涉及的基础，包括与年龄相关的萎缩。探索IL-22介导的再生的功能翻译是我博士后工作的自然发展，它将构成该提案的K99指导阶段。这些研究的逻辑扩展，探讨了IL-22再生途径的潜在机制和含义，将在该提案的独立R00阶段进行探索。 The mechanistic and pre-clinical studies outlined in this proposal have the potential to define an important novel pathway in thymic regeneration, which could result in clinical approaches to enhance T cell immunity, not only for recipients of allo-HSCT, but also for individuals with T cell deficiencies due to aging (lymphoid atrophy), autoimmune diseases, genetic causes (such as SCID), infectious diseases （HIV，肝炎B/C），皮质类固醇，休克，放射或化学治疗和放射损伤（核事故或恐怖主义）。