Targeting IL-18 in Thymic Regeneration

摘要 以IL-18为靶点的胸腺再生 胸腺是负责T细胞发育的器官，对急性损伤和 能够再生的。然而，随着年龄的增长，胸腺逐渐丧失其功能，以至于有 即使在成年初期，T细胞的产生能力和损伤恢复能力也明显下降。这个 胸腺对造血干细胞移植(HCT)前的细胞还原条件特别敏感。 因此，移植受者机会性感染和恶性肿瘤复发的风险增加。 在长时间的T细胞缺乏期。目前尚无经临床批准的改善策略 胸腺功能和治疗淋巴细胞减少症。更好地了解胸腺损伤的内源性途径和 再生可能为这一目的的治疗策略提供信息。 在这里，我们提供了证据支持热下垂诱导的白介素18(IL-18)作为一种 急性损伤后胸腺生成的负性调节因子及其对改善器官功能的靶向性 在淋巴细胞减少的情况下。这项研究的目的1是调查急性胰腺炎后这种抑制IL-18的来源 亚致死剂量辐射损伤(SL-TBI)及其下游细胞效应因子。具体地说，我们调查 胸腺内的胸腺上皮细胞和固有淋巴样细胞作为IL-18的效应者的S机制 行动。本研究的目的2提出了使用抗IL-18单抗对IL-18信号的时间衰减 抗体作为一种新的治疗策略来改善胸腺恢复，并随后改善外周T细胞 重组和功能。我提出了临床相关的移植模型，以评估其潜在的 改善血细胞移植后的再生。此外，我将评估阻断IL-18信号在老年人中的可能性 胸腺退化的模型。总而言之，这些研究不仅将提供对生物机制的洞察 组织损伤和修复，但也将提供一种创新的治疗策略，以提高免疫功能 特别是在接受血细胞移植的人中。

ABSTRACT Targeting IL-18 in Thymic Regeneration The thymus, the organ responsible for T cell development, is both highly sensitive to acute injury and capable of regeneration. However, the thymus progressively loses its function with age such that there is markedly reduced capacity for T cell production and recovery from damage even early in adulthood. The thymus is particularly sensitive to pre-hematopoietic stem cell transplant (HCT) cytoreductive conditioning. Therefore, transplant recipients are at increased risk of opportunistic infection as well as relapse of malignancy during a prolonged period of T cell deficiency. No clinically approved strategies currently exist to improve thymic function and treat lymphopenia. Better understanding endogenous pathways of thymic damage and regeneration may inform therapeutic strategies to this end. Here, we provide evidence supporting the involvement of pyroptosis induced interleukin-18 (IL-18) as a negative regulator of thymopoieisis following acute injury and propose its targeting for improving organ function in settings of lymphopenia. Aim 1 of this study investigates the source of this suppressive IL-18 following acute damage by sublethal irradiation (SL-TBI) and its downstream cellular effectors. Specifically, we investigate thymic epithelial cells (TECs) and innate lymphoid cells within the thymus as effectors of IL-18’s mechanism of action. Aim 2 of this study proposes the temporal attenuation of IL-18 signaling using anti IL-18 monoclonal antibody as a novel therapeutic strategy to improve thymic recovery, and subsequently, peripheral T cell reconstitution and function. I put forward clinically relevant transplant models to assess its potential for improving regeneration post-HCT. Additionally, I will assess the potential of blocking IL-18 signaling in aged models of thymic involution. Together, these studies will not only provide insight into the biological mechanisms of tissue injury and repair, but also will offer an innovative therapeutic strategy to boost immune function especially in recipients of HCT.