Harnessing endogenous mechanisms of thymic regeneration toboost immune function in recipients of hematopoietic cell transplant

项目总结 尽管胸腺对急性损伤非常敏感，如感染、休克、 或常见的癌症治疗方法，如细胞减少性化疗或放射疗法，它也有显著的 内源性修复能力。尽管有持续的胸腺退化和再生来回应 日常的侮辱，如压力和感染，常见癌症造成的急性和严重的胸腺损伤 作为造血细胞移植(HCT)的一部分，治疗和调理方案会导致 长期T细胞缺乏；导致机会性感染的高发病率和死亡率，并可能 甚至会促进癌症复发。此外，这种再生能力随着年龄的增长而进一步下降。 我们之前已经确定了两条独立的内源性胸腺再生途径，集中在 天然淋巴样细胞(ILCs)产生再生相关因子(RAF)IL-22，以及 BMP4由内皮细胞(ECs)介导；两者都通过靶向胸腺上皮来介导其再生效应 细胞。尽管我们和其他人之前已经发现树突状细胞(DC)产生的IL-23对 控制ILC产生IL-22，触发再生反应的基本机制 通过这些不同的RAF的产生，人们对此知之甚少。在我们的初步数据中，我们已经证明 模式识别受体NOD2的缺失导致IL-2的产生显著增加 22、IL-23和BMP4，促进全身照射后胸腺损伤的恢复。这 提示在稳态条件下，NOD2信号会抑制这些再生细胞的产生 细胞因子；但损伤后，这种负面刺激被移除，从而通过激活细胞因子来实现组织修复 RAF的生产。基于这些发现，我们假设(A)DC和DCs中固有的NOD2信号 ECS分别抑制IL-23和BMP4的产生；(B)NOD2介导的抑制 RAF在受损后因胸腺细胞的耗尽而被取消；以及(C)这一共同的途径 再生可以成为促进HCT后胸腺功能的一种更好的方法。 具体地说，我们的建议有以下目的：(1)研究NOD2在调节 急性损伤后内源性胸腺再生；(2)确定NOD2信号的调节因子 抑制RAF的稳态产生；以及(3)研究这些途径是否可以作为一种 促进同种异体移植后T细胞重建的方法 这项提案中概述的机械性和临床前研究不仅有可能定义 组织再生的重要新途径，但也可能导致创新的临床方法 促进HCT受者以及胸腺受损患者的T细胞重建 由于年龄、感染或其他细胞减少性癌症治疗。

PROJECT SUMMARY Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable capacity for endogenous repair. Although there is continual thymic involution and regeneration in response to everyday insults like stress and infection, acute and profound thymic damage caused by common cancer therapies and the conditioning regimes used as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines further as a function of age. We have previously identified two independent pathways of endogenous thymic regeneration, centered on the production of the regeneration-associated factors (RAFs) IL-22 by innate lymphoid cells (ILCs), and BMP4 by endothelial cells (ECs); both of which mediate their regenerative effects by targeting thymic epithelial cells. Although we and others have previously identified dendritic cell (DC)-produced IL-23 as critical for controlling the production of IL-22 by ILCs, the underlying mechanisms that trigger the regenerative response via the production of these distinct RAFs is poorly understood. In our preliminary data we have demonstrated that deletion of the pattern recognition receptor NOD2 results in a significant increase in the production of IL- 22, IL-23, and BMP4, leading to improved thymus recovery after damage caused by total body irradiation. This suggests that under steady-state conditions, NOD2 signaling suppresses the production of these regenerative cytokines; but after damage this negative stimulus is removed, thereby enabling tissue repair by activating the production of RAFs. Based on these findings, we hypothesize that (a) intrinsic NOD2 signaling in DCs and ECs suppresses the production of IL-23 and BMP4, respectively; (b) NOD2-mediated suppression of RAFs is abolished after damage by the depletion of thymocytes; and (c) that this common pathway of regeneration can be exploited into a superior method to promote thymic function following HCT. Specifically, our proposal has the following aims: (1) To investigate the role of NOD2 in regulating endogenous thymic regeneration after acute damage; (2) To identify the regulators of NOD2 signaling that suppress the steady-state production of RAFs; and (3) To study if these pathways can be modulated as a means of improving T cell reconstitution following HCT. The mechanistic and pre-clinical studies outlined in this proposal not only have the potential to define important novel pathways underlying tissue regeneration, but could also result in innovative clinical approaches to enhance T cell reconstitution in recipients of HCT, as well as patients whose thymus has been decimated due to age, infection or other cytoreductive cancer therapies.