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

利用胸腺再生的内源机制增强造血细胞移植受者的免疫功能

• 批准号: 10545013
• 负责人: Jarrod Dudakov
• 金额: $ 40.75万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545013
• 关键词: Acute; Address; Age; Aging; Apoptotic; Autoimmune Diseases; BMP4; Cancer Relapse; Cells; Cellularity; Clinical; Communicable Diseases; Data; Dendritic Cells; Development; Endothelial Cells; Family member; Genetic; Goals; Immune; Immunity; Immunocompetence; Immunotherapy; Individual; Infection; Injury; Link; Lymphoid Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Natural regeneration; Nuclear Accidents; Opportunistic Infections; Pathway interactions; Patients; Pattern recognition receptor; Persons; Pharmacology; Population Heterogeneity; Process; Production; Radiation Injuries; Radiation therapy; Recovery; Regenerative capacity; Regenerative pathway; Regenerative response; Regulation; Role; Shock; Signal Transduction; Stimulus; Stress; Stromal Cells; T cell reconstitution; T-Lymphocyte; Terrorism; Testing; Therapeutic; Therapeutic Studies; Thymic epithelial cell; Thymus Gland; Vaccines; Whole-Body Irradiation; Work; aged; base; cancer therapy; chemotherapy; clinically relevant; conditioning; cytokine; emerging pathogen; hematopoietic cell transplantation; immune function; improved; innovation; interleukin-22; interleukin-23; mortality; novel; novel therapeutic intervention; preclinical study; regenerative; repaired; response; restoration; rho GTP-Binding Proteins; severe injury; thymic regeneration; thymocyte; tissue regeneration; tissue repair

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.

项目摘要 即使胸腺对急性损伤非常敏感，例如感染，冲击，震动， 或常见的癌症疗法，例如细胞保减化学或放射疗法，它也具有显着的 内源性修复的能力。尽管响应于 日常侮辱，例如由普通癌症造成的压力和感染，急性和深刻的胸腺损伤 疗法和用作造血细胞移植（HCT）一部分的条件状态导致 长时间的T细胞缺乏；从机会感染引起高发病和死亡率，可能 甚至促进癌症复发。此外，这种再生能力随着年龄的函数而进一步下降。 我们以前已经确定了内源性胸腺再生的两种独立途径，以中心为中心 关于先天淋巴样细胞（ILC）的生产再生相关因子（RAFS）IL-22 BMP4由内皮细胞（ECS）；两者都通过靶向胸腺上皮来介导其再生作用 细胞。尽管我们和其他人以前已经确定了树突状细胞（DC）生产的IL-23对 控制ILC的IL-22的产生，ILC是触发再生反应的基本机制 通过生产这些独特的Rafs，人们对此很少了解。在我们的初步数据中，我们已经证明了 模式识别受体NOD2的删除导致IL-产生显着增加 22，IL-23和BMP4，导致全体辐射造成的损害后，胸腺恢复得到改善。这 表明在稳态条件下，NOD2信号抑制了这些再生的产生 细胞因子；但是在损坏后，消除了这种负刺激，从而通过激活 生产RAFS。基于这些发现，我们假设（a）DC和 EC分别抑制IL-23和BMP4的产生； （b）NOD2介导的抑制 胸腺细胞耗竭后，消除了皇家贸易室。 （c）这种常见的途径 可以将再生利用为促进HCT促进胸腺功能的卓越方法。 具体而言，我们的建议具有以下目的：（1）调查NOD2在调节中的作用 急性损伤后内源性胸腺再生； （2）确定NOD2信号的调节剂 抑制RAFS的稳态生产； （3）研究这些途径是否可以调制为 HCT后改善T细胞重建的手段。 该提案中概述的机械和临床前研究不仅有可能定义 重要的新型组织再生途径，但也可能导致创新的临床方法 为了增强HCT接受者的T细胞重建，以及胸腺已衰落的患者 由于年龄，感染或其他细胞保减癌疗法。