Targeting IL-18 in Thymic Regeneration

胸腺再生中的靶标 IL-18

基本信息

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
项目类别：
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

项目摘要

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.

抽象的胸腺再生中的靶标 IL-18 胸腺是负责 T 细胞发育的器官，对急性损伤和然而，随着年龄的增长，胸腺逐渐丧失其功能。即使在成年早期，T 细胞的产生和从损伤中恢复的能力也显着降低。胸腺对造血干细胞移植前（HCT）细胞减灭调节特别敏感。因此，移植受者发生机会性感染以及恶性肿瘤复发的风险增加目前尚无临床批准的改善 T 细胞缺陷的策略。胸腺功能和治疗淋巴细胞减少症更好地了解胸腺损伤和的内源性途径。再生可能会为此目的提供治疗策略。在这里，我们提供的证据支持焦亡诱导的白细胞介素 18 (IL-18) 作为一种参与急性损伤后胸腺生成的负调节因子及其改善器官功能的建议本研究的目标 1 调查急性淋巴细胞减少症后这种抑制性 IL-18 的来源。具体而言，我们研究了亚致死照射（SL-TBI）及其下游细胞效应物造成的损伤。胸腺上皮细胞 (TEC) 和胸腺内的先天淋巴细胞作为 IL-18 机制的效应器本研究的目标 2 提出使用抗 IL-18 单克隆抗体暂时减弱 IL-18 信号传导。抗体作为一种新的治疗策略来改善胸腺恢复，以及随后的外周 T 细胞我提出了临床相关的移植模型来评估其潜力。此外，我将评估阻断老年人中 IL-18 信号传导的潜力。这些研究不仅将提供对胸腺退化模型的深入了解。组织损伤和修复，同时也将提供一种创新的治疗策略来增强免疫功能尤其是 HCT 接受者。