IL-22 in Thymic Regeneration

描述（由申请方提供）：胸腺的内源性再生是一种关键功能，可在感染、休克、细胞减少性化疗或放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减弱，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，以便它们可以被利用到临床相关的免疫复壮策略。这对于异基因造血干细胞移植（allo-HSCT）的接受者尤其相关，其经历由细胞减少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，这导致感染和恶性复发的发病率和死亡率增加。 白细胞介素-22（IL-22）由T辅助细胞（Th）17和先天性淋巴样细胞（ILC）产生，并促进肠、肺和皮肤中上皮细胞的先天性免疫和稳态。我们已经发现了一个新的作用，IL-22在胸腺损伤后的胸腺上皮细胞（TECs）的内源性再生。我们发现，IL-22对于稳态胸腺生成是多余的，但在胸腺损伤后，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）胸腺树突状细胞（tDC）产生的IL-23增加，并可增强先天淋巴细胞产生的IL-22，和d）IL-22给药可增强总体胸腺细胞构成以及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细胞发育早在骨髓（BM）造血干细胞和祖细胞（HSPC）。基于这些发现，我们假设（a）IL-22在胸腺损伤后的内源性T细胞再生中起重要作用，（B）IL-22促进HSPC向淋巴系的分化和定型，以及（c）IL- 22可用作临床中的治疗策略以在免疫耗竭后增强胸腺功能。 我们的建议有以下目的：（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在前胸腺淋巴定向和发育中的作用，和（3）研究IL-22给药改善allo-HSCT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，这可能导致临床方法来增强T细胞免疫，不仅用于allo-HSCT受体，而且用于T细胞免疫缺陷的个体。 由于衰老（淋巴萎缩）、自身免疫性疾病、传染病、休克、放射或化学疗法和辐射损伤（核事故或恐怖主义）引起的缺陷。

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).