IL-22 in Thymic Regeneration

描述(由申请人提供)：胸腺的内源性再生是一种重要的功能，它允许在感染、休克、细胞减少性化疗或放射治疗和其他原因导致胸腺损伤后恢复免疫能力。胸腺的再生能力随着年龄的增长而减弱，这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，以便将其用于临床相关的免疫恢复策略。这与异基因造血干细胞移植(allo-HSCT)的受者尤其相关，他们在移植后由于细胞还原调节和移植物抗宿主病(GVHD)而经历长期的T细胞缺陷，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细胞(Th)17细胞和天然淋巴样细胞(ILCs)产生，促进肠道、肺和皮肤上皮细胞的天然免疫和动态平衡。我们发现了IL-22在胸腺损伤后胸腺上皮细胞(TECs)内源性再生中的新作用。我们发现，IL-22对于稳定状态的胸腺生成是多余的，但在胸腺损伤后，a)胸腺中IL-22的绝对水平增加，b)胸腺ILCs(TILCs)产生IL-22增加，c)胸腺树突状细胞(TDCs)产生IL-23增加，并能促进固有淋巴样细胞产生IL-22，d)IL-22治疗可提高胸腺整体细胞密度和TECs的增殖和存活。我们的初步发现还表明，IL-22可以影响T细胞的发育，早在骨髓(BM)、造血干细胞和祖细胞(HSPC)就可以影响。基于这些发现，我们推测：(A)IL-22在胸腺损伤后内源性T细胞再生中发挥重要作用，(B)IL-22促进HSPC向淋巴系的分化和承诺，以及(C)IL-22可作为临床上用于增强免疫耗竭后胸腺功能的治疗策略。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在胸腺前淋巴承诺和发育中的作用；(3)研究IL-22应用于促进异基因HSCT后T细胞重建的可能性。这项建议中概述的机制和临床前研究有可能确定胸腺再生的一条重要的新途径，这可能导致临床方法来增强T细胞免疫，不仅适用于allo-HSCT的接受者，也适用于T细胞携带者。 由于衰老(淋巴萎缩)、自身免疫性疾病、传染病、休克、放射或化疗和辐射损伤(核事故或恐怖主义)造成的缺陷。

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).