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: 10656565
• 负责人: Jarrod Dudakov
• 金额: $ 57.05万
• 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/10656565
• 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; Methods; Modeling; Morbidity - disease rate; Natural regeneration; Nuclear Accidents; Opportunistic Infections; Pathway interactions; Patients; Pattern recognition receptor; Persons; 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; 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; pharmacologic; 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 尽管胸腺对感染、休克等急性损伤非常敏感， 或常见的癌症治疗，如细胞减少性化疗或放射治疗，它也有显着的 内源性修复能力。尽管胸腺持续退化和再生， 日常的侮辱，如压力和感染，急性和深刻的胸腺损伤所造成的常见癌症 作为造血细胞移植（HCT）的一部分使用的治疗和调节方案，导致 长期的T细胞缺乏症;诱发机会性感染的高发病率和死亡率， 甚至促进癌症复发。此外，这种再生能力随着年龄的增长而进一步下降。 我们以前已经确定了两个独立的途径内源性胸腺再生， 对先天性淋巴样细胞（ILC）产生再生相关因子（RAFs）IL-22的影响，和 BMP 4通过内皮细胞（EC）;两者都通过靶向胸腺上皮细胞介导其再生作用 细胞尽管我们和其他人先前已经确定树突状细胞（DC）产生的IL-23对 控制ILC产生IL-22，这是触发再生反应的潜在机制， 通过这些不同的RAF的生产是知之甚少。在我们的初步数据中， 模式识别受体NOD 2的缺失导致IL-2的产生显著增加， 22、IL-23和BMP 4，导致全身照射引起的损伤后改善的胸腺恢复。这 这表明，在稳态条件下，NOD 2信号抑制这些再生的生产， 细胞因子;但在损伤后，这种负刺激被去除，从而通过激活细胞因子使组织修复成为可能。 生产RAF。基于这些发现，我们假设：（a）DC中的内源性NOD 2信号转导， EC分别抑制IL-23和BMP 4的产生;（B）NOD 2介导的对IL-23和BMP 4的抑制。 RAFs在损伤后通过胸腺细胞的消耗而被消除;和（c）RAFs的这种共同途径在胸腺细胞的损伤后被消除。 再生可被开发成促进HCT后胸腺功能的上级方法。 具体而言，我们的建议有以下目的：（1）研究NOD 2在调节 急性损伤后内源性胸腺再生;（2）鉴定NOD 2信号转导的调节因子， 抑制RAFs的稳态产生;（3）研究这些途径是否可以作为一种调节因子进行调节。 改善HCT后T细胞重建的方法。 本提案中概述的机制和临床前研究不仅有可能定义 重要的新途径，但也可能导致创新的临床方法 增强HCT接受者以及胸腺被破坏的患者的T细胞重建 由于年龄、感染或其他细胞减少性癌症治疗。