Targeting trained immunity in transplantation

在移植中瞄准经过训练的免疫力

• 批准号: 10642592
• 负责人: Zahi A. Fayad
• 金额: $ 301.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642592
• 关键词: Allografting; Amplifiers; Animals; Authorization documentation; Autoimmune Diseases; Automobile Driving; B-Lymphocytes; Bioinformatics; Biology; Biomedical Engineering; Biopsy; Bone Marrow; Bone Marrow Diseases; Cells; Cellular Assay; Chronic; Clinical; Clinical Data; Clinical Research; Data; Diagnosis; Epigenetic Process; Future; Graft Rejection; Heart Transplantation; Hematopoietic; Hematopoietic stem cells; Human; Image; Immune; Immune Tolerance; Immunity; ImmunoPET; Immunologic Memory; Immunology; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Kidney; Kidney Transplantation; Link; Mediating; Metabolic; Metabolism; Modeling; Modernization; Modification; Monitor; Mus; Myeloid Cells; Myelopoiesis; Nanotechnology; Natural Immunity; Organ failure; Patients; Peripheral Blood Mononuclear Cell; Play; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Publishing; Regimen; Research Personnel; Role; Scientist; System; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic immunosuppression; Time; Toxic effect; Training; Translating; Transplant Recipients; Transplant-Related Disorder; Transplantation; Validation; Visualization; Work; allograft rejection; allotransplant; antimicrobial; authority; cancer risk; clinically relevant; computerized data processing; design; fluorodeoxyglucose positron emission tomography; heart allograft; image translation; imaging approach; imaging modality; immune activation; in vivo; innovation; insight; isoimmunity; monocyte; multidisciplinary; multiple omics; nanobiologic; nanotherapeutic; nanotherapy; non-invasive imaging; nonhuman primate; novel; novel therapeutic intervention; organ transplant rejection; pre-clinical; preclinical study; prevent; progenitor; programs; response; side effect; success; synergism; systemic inflammatory response; therapeutic target; tool

SUMMARY – OVERVIEW Transplantation has revolutionized the lives of patients suffering from organ failure. The design of modern immunosuppression has employed a time-honored focus on controlling T cell-mediated responses. However, current immunosuppressive therapies have suboptimal success rates and induce significant side effects, including increased susceptibility to infections, metabolic toxicity, and cancer risk. Given the growing body of evidence showing that innate immunity is also critical to alloresponse initiation and allograft survival, it is not surprising that current immunosuppressive regimens do not achieve satisfactory long-term graft and patient survival. Recent work by this P01’s investigators has shown that trained immunity plays a vital role in allograft survival. Trained immunity is a long-term increase in the functional responsiveness of innate immune cells, which is maintained by epigenetic modifications and can be considered de facto innate immune memory. On a systems level, we demonstrated that trained immunity is regulated and maintained by epigenetic modifications in bone marrow hematopoietic progenitors, which consequently release trained innate immune cells with augmented inflammatory and antimicrobial function. Our preclinical and clinical preliminary data revealed a discrete causative connection between allograft transplantation, the induction of trained immunity, systemic inflammatory response, and activated or amplified T cell-mediated alloimmunity. Furthermore, we identified trained immunity as a compelling therapeutic target in mouse and non-human primate heart allograft models. Based on these results, our central hypothesis is that trained immunity is a critical mechanism that amplifies and sustains both innate and adaptive rejection responses and is therefore a compelling clinical therapeutic target for achieving long-term allograft survival without requiring chronic immunosuppression. In this P01, we will address our central hypothesis by drawing on the expertise of authorities in the fields of immunology and bioengineering. This multidisciplinary team of scientists and clinicians will work together to i) understand trained immunity’s clinical relevance in kidney transplantation, ii) elucidate the mechanisms by which trained immunity is induced and leads to organ rejection, and iii) develop bioengineering solutions for diagnosing and therapeutically regulating trained immunity in transplantation. We anticipate that, together, these highly interactive Projects will generate innovative new therapeutic strategies to more effectively prevent rejection and potentially achieve immune tolerance. If successful, these studies could impact the entire field of transplantation and provide insights that could also be highly relevant for bone marrow transplantation and autoimmune disease.

摘要 – 概述 移植彻底改变了器官衰竭患者的生活。现代的设计 免疫抑制长期以来一直专注于控制 T 细胞介导的反应。然而， 目前的免疫抑制疗法的成功率不佳，并会产生明显的副作用， 包括增加对感染、代谢毒性和癌症风险的易感性。鉴于日益增长的身体 有证据表明先天免疫对于同种异体反应的启动和同种异体移植物的存活也至关重要，但事实并非如此 令人惊讶的是，目前的免疫抑制方案并未达到令人满意的长期移植物和患者的效果 生存。 P01 研究人员最近的工作表明，训练有素的免疫力在同种异体移植中发挥着至关重要的作用 生存。训练有素的免疫力是先天免疫功能反应能力的长期提高 细胞，通过表观遗传修饰维持，可以被认为是事实上的先天免疫 记忆。在系统层面上，我们证明了受过训练的免疫力是由表观遗传调节和维持的 骨髓造血祖细胞发生改变，从而释放经过训练的先天造血祖细胞 具有增强炎症和抗菌功能的免疫细胞。我们的临床前和临床初步 数据揭示了同种异体移植、受过训练的诱导之间存在离散的因果关系 免疫、全身炎症反应以及激活或增强的 T 细胞介导的同种免疫。 此外，我们发现训练有素的免疫力是小鼠和非人类灵长类动物的一个引人注目的治疗目标 心脏同种异体移植模型。基于这些结果，我们的中心假设是训练有素的免疫力是一个关键 放大和维持先天性和适应性拒绝反应的机制，因此是一种 令人信服的临床治疗目标，无需慢性治疗即可实现长期同种异体移植存活 免疫抑制。 在本 P01 中，我们将利用以下领域权威的专业知识来解决我们的中心假设： 免疫学和生物工程。这个由科学家和临床医生组成的多学科团队将共同努力 i) 了解经过训练的免疫在肾移植中的临床相关性，ii) 通过以下方式阐明其机制 诱导训练有素的免疫力并导致器官排斥，以及 iii) 开发生物工程解决方案 诊断和治疗调节移植中训练有素的免疫力。 我们预计，这些高度互动的项目将共同产生创新的新治疗策略 更有效地防止排斥反应并可能实现免疫耐受。如果成功的话，这些研究可以 影响整个移植领域并提供与骨髓高度相关的见解 移植和自身免疫性疾病。