Targeting IL-18 in Thymic Regeneration

胸腺再生中的靶标 IL-18

• 批准号: 10676524
• 负责人: David William Granadier
• 金额: $ 4.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-16 至 2025-06-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676524
• 关键词: Acute; Adolescent; Adult; Age; Aging; Apoptotic; Attention; Biological; CASP1 gene; Cell Death; Cells; Chronic; Clinical; Data; Detection; Exposure to; Hematopoietic Stem Cell Transplantation; IL18 gene; Immune; Immune response; Immunocompetence; Immunologic Deficiency Syndromes; Incidence; Infection; Inflammatory; Injury; Ionizing radiation; Lymphoid Cell; Lymphopenia; Lytic; Malignant - descriptor; Malignant Neoplasms; Mediator; Modeling; Molecular; Monoclonal Antibodies; Natural regeneration; Opportunistic Infections; Organ; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Population; Process; Production; Productivity; Recovery; Regenerative capacity; Relapse; Reporting; Risk; Risk Factors; Role; Signal Transduction; Source; Stem cell transplant; Stimulus; Stress; T cell reconstitution; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Therapeutic; Thymic epithelial cell; Thymus Gland; Tissues; Transplant Recipients; Transplantation; Whole-Body Irradiation; age related; aged; aging population; attenuation; cancer therapy; clinically relevant; conditioning; constriction; cytokine; immune function; immune reconstitution; immunogenic cell death; improved; innovation; insight; interleukin-23; irradiation; mortality; novel therapeutic intervention; preclinical study; preconditioning; regenerative; repaired; restoration; therapeutic target; thymic regeneration; thymocyte; tissue injury; tissue regeneration; tissue repair; transplant model; vaccine response

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.

摘要 靶向IL-18参与胸腺再生 胸腺是负责T细胞发育的器官，对急性损伤高度敏感， 能够再生。然而，胸腺随着年龄的增长逐渐丧失其功能， 显著降低T细胞产生和从损伤中恢复的能力，甚至在成年早期。的 胸腺对造血干细胞移植（HCT）前的细胞减少调节特别敏感。 因此，移植受者机会性感染和恶性肿瘤复发的风险增加 在T细胞缺乏的长期期间。目前没有临床批准的策略来改善 胸腺功能和治疗淋巴细胞减少症。更好地理解胸腺损伤的内源性途径， 再生可以告知为此目的的治疗策略。 在这里，我们提供的证据支持参与焦亡诱导的白细胞介素-18（IL-18），作为一个 急性损伤后胸腺生成的负调节因子，并提出其改善器官功能的靶向 在淋巴细胞减少的情况下。本研究的目的1是研究急性心肌梗死后这种抑制性IL-18的来源。 亚致死辐射损伤（SL-TBI）及其下游细胞效应物。具体来说，我们调查 胸腺内的胸腺上皮细胞（TEC）和先天性淋巴样细胞作为IL-18的免疫调节机制的效应物， 行动上本研究的目的2提出使用抗IL-18单克隆抗体对IL-18信号转导进行时间衰减 抗体作为一种新的治疗策略，以改善胸腺恢复，并随后，外周T细胞 重建和功能。我提出了临床相关的移植模型来评估其潜力， 改善HCT后的再生。此外，我将评估阻断IL-18信号转导在老年人中的潜力。 胸腺退化模型。总之，这些研究不仅可以深入了解生物学机制， 组织损伤和修复，还将提供一种创新的治疗策略，以提高免疫功能， 特别是在HCT的接受者中。