IL-22 in Thymic Regeneration

IL-22 在胸腺再生中的作用

• 批准号: 8477127
• 负责人: Marcel R M van den Brink
• 金额: $ 47.25万
• 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: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477127
• 关键词: Affect; Age; Aging; Allogenic; Animals; Area; Atrophic; Autoimmune Diseases; Bone Marrow; Cell physiology; Cells; Cellularity; Clinic; Clinical; Communicable Diseases; Competence; Dendritic Cells; Development; Epithelial Cells; Genetic; Goals; Hematopoietic; Hematopoietic Stem Cell Transplantation; Homeostasis; Immune; Immune system; Immunity; Individual; Infection; Injury; Intestines; Lung; Lymphoid; Lymphoid Cell; Malignant - descriptor; Morbidity - disease rate; Natural Immunity; Natural regeneration; Nuclear Accidents; Outcome; Pathway interactions; Peripheral; Play; Process; Production; Radiation; Radiation Injuries; Radiation therapy; Radio; Recovery; Regulation; Rejuvenation; Relapse; Role; Shock; Signal Transduction; Skin; Source; Stem cells; T-Cell Development; T-Lymphocyte; Terrorism; Therapeutic; Therapeutic Studies; Thymic epithelial cell; Thymus Gland; Transplantation; age related; base; chemotherapy; clinically relevant; conditioning; cytokine; experience; graft vs host disease; graft vs leukemia effect; improved; innovation; interleukin-22; interleukin-23; mortality; novel; preclinical study; reconstitution; regenerative; repaired; stem

DESCRIPTION (provided by applicant): Endogenous regeneration of the thymus is a crucial function that allows for renewal of immune competence following infection, shock, cytoreductive chemo- or radiation therapy and other causes of thymic injury. Thymic regenerative capacity diminishes with age and remains a poorly understood area. One of the major goals of this project is to elucidate the processes of endogenous thymic regeneration so that they may be exploited into clinically relevant strategies for immune rejuvenation. This is particularly relevan 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. Interleukin-22 (IL-22) 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 found a novel role for IL-22 in the endogenous regeneration of thymic epithelial cells (TECs) after thymic damage. We found that IL-22 was redundant for steady-state thymopoiesis but following thymic damage a) absolute levels of IL-22 in the thymus were increased, b) IL-22 production by thymic ILCs (tILCs) was increased, c) IL-23 production by thymic dendritic cells (tDCs) was increased and could enhance IL-22 production by innate lymphoid cells, and d) IL-22 administration could enhance overall thymic cellularity and proliferation and survival of TECs. Our preliminary findings also suggest that IL-22 can affect T cell development as early as bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). Based on these findings, we hypothesize that (a) IL-22 plays an important role in endogenous T cell regeneration following thymic insult, (b) IL-22 promotes differentiation and commitment of HSPCs to the lymphoid lineage, and (c) IL- 22 can be utilized as a therapeutic strategy in the clinic to boost thymic function following immune depletion. Our proposal has the following aims: (1) To study the role of IL-22 in endogenous regeneration of thymopoiesis, (2) To study the role of IL-22 in pre-thymic lymphoid commitment and development, and (3) To study the potential for IL-22 administration to improve T cell reconstitution following allo-HSCT. 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, infectious diseases, 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项至关重要的功能，可以在感染、休克、细胞减灭性化疗或放疗以及胸腺损伤的其他原因后恢复免疫能力。胸腺的再生能力随着年龄的增长而减弱，并且仍然是一个知之甚少的领域。该项目的主要目标之一是阐明内源性胸腺再生的过程，以便将它们用于临床相关的免疫复兴策略。这对于同种异体造血干细胞移植 (allo-HSCT) 的受者尤其重要，他们经历了由细胞减灭性调节和移植物抗宿主病 (GVHD) 引起的长期移植后 T 细胞缺乏，导致感染和恶性复发的发病率和死亡率增加。 白介素 22 (IL-22) 由辅助性 T (Th)17 细胞和先天性淋巴细胞 (ILC) 产生，可促进先天免疫以及肠、肺和皮肤上皮细胞的稳态。我们发现 IL-22 在胸腺损伤后胸腺上皮细胞 (TEC) 的内源性再生中发挥新作用。我们发现IL-22对于稳态胸腺生成是多余的，但胸腺损伤后a）胸腺中IL-22的绝对水平增加，b）胸腺ILC（tILC）产生的IL-22增加，c）胸腺树突细胞（tDC）产生的IL-23增加，并且可以增强先天淋巴细胞产生IL-22，d）IL-22给药 可以增强整体胸腺细胞结构以及 TEC 的增殖和存活。我们的初步研究结果还表明，IL-22 可以影响 T 细胞的发育，早至骨髓 (BM) 造血干细胞和祖细胞 (HSPC) 的发育。基于这些发现，我们假设 (a) IL-22 在胸腺损伤后的内源性 T 细胞再生中发挥重要作用，(b) IL-22 促进 HSPC 向淋巴谱系的分化和定型，以及 (c) IL-22 可用作临床治疗策略，以增强免疫耗竭后的胸腺功能。 我们的提案有以下目的：（1）研究IL-22在胸腺生成的内源性再生中的作用，（2）研究IL-22在前胸腺淋巴样定型和发育中的作用，以及（3）研究IL-22给药改善同种异体造血干细胞移植后T细胞重建的潜力。该提案中概述的机制和临床前研究有可能定义胸腺再生的重要新途径，这可能导致增强 T 细胞免疫的临床方法，不仅适用于同种异体造血干细胞移植的受者，也适用于 T 细胞个体 由于衰老（淋巴萎缩）、自身免疫性疾病、传染病、休克、放疗或化疗以及辐射损伤（核事故或恐怖主义）而导致的缺陷。