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种关键功能，可在感染，休克，细胞减退性化学或放射治疗以及其他胸腺损伤原因后更新免疫能力。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。该项目的主要目标之一是阐明内源性胸腺再生的过程，以便将它们利用为临床相关的免疫恢复策略。这对于同种异体造血干细胞移植（Allo-HSCT）的接受者尤其重要，他们经历了由细胞调节性调节和接枝抗抗抗癌疾病（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产生的发病率增加。 白介素-22（IL-22）由T馆（Th）17个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。我们发现IL-22在胸腺损伤后胸腺上皮细胞（TEC）的内源性再生中的新作用。我们发现，对于稳态胸腺甲状腺素，IL-22是多余的，但是胸膜损伤a）胸腺中胸腺中IL-22的绝对水平增加，b）胸膜ILC（TILC）的IL-22产生增加，c）增加，c）IL-23产生IL-23由胸膜树状细胞增强，并增加了Dendritic的生产（TDCS），而ILTAIL可能会增加IL-22 IL-22 l-22 l-22 l-22 l-22 l-22。可以增强TEC的总体胸腺细胞性，增殖和生存。我们的初步发现还表明，IL-22早在骨髓（BM）造血干细胞和祖细胞（HSPC）就可以影响T细胞的发育。基于这些发现，我们假设（a）IL-22在胸腺损伤后（a）IL-22在内源性T细胞再生中起重要作用，（b）IL-22促进了HSPC对淋巴机谱系的分化和承诺，并且（c）IL- 22可用于遵循临床功能，从而使thymic thymic thymic them them themic themic themic themic them themics themics themic teclune cartune temim clune tement temenne carnem themic cartune。 我们的提议具有以下目的：（1）研究IL-22在胸腺甲基膜的内源性再生中的作用，（2）研究IL-22在胸膜前淋巴机前的承诺和发育中的作用，以及（3）研究IL-22给药的潜力，以改善Allo-HSCT后改善T细胞重新构造。该提案中概述的机械和临床前研究具有定义胸腺再生中重要的新途径的潜力，这可能会导致临床方法增强T细胞免疫，而不仅仅是针对Allo-HSCT的接受者，而且对于具有T细胞的个体而言， 由于衰老（淋巴萎缩），自身免疫性疾病，感染性疾病，休克，无线电或化学治疗和放射损伤（核事故或恐怖主义）引起的缺陷。