Targeting trained immunity in transplantation

摘要-概述 器官移植彻底改变了器官衰竭患者的生活。设计现代 免疫抑制已经采用了历史悠久的焦点来控制T细胞介导的应答。然而，在这方面， 目前的免疫抑制疗法具有次优的成功率并引起显著的副作用， 包括对感染、代谢毒性和癌症风险的易感性增加。鉴于越来越多的 有证据表明，先天免疫对同种异体反应的启动和同种异体移植物的存活也是至关重要的， 令人惊讶的是，目前的免疫抑制方案不能实现令人满意的长期移植物和患者 生存 P01研究者最近的工作表明，训练的免疫力在同种异体移植中起着至关重要的作用。 生存训练免疫是先天免疫系统功能反应性的长期增强， 细胞，这是维持表观遗传修饰，可以被认为是事实上的先天免疫 记忆在系统水平上，我们证明了训练的免疫力是由表观遗传调节和维持的。 在骨髓造血祖细胞的修饰，从而释放训练的先天 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 数据显示，同种异体移植，诱导训练， 免疫、全身炎症反应和活化或扩增的T细胞介导的同种异体免疫。 此外，我们确定训练免疫作为一个引人注目的治疗目标，在小鼠和非人灵长类动物 心脏移植模型。基于这些结果，我们的中心假设是，训练的免疫是一个关键的 放大和维持先天和适应性排斥反应的机制，因此是一种 令人信服的临床治疗目标，以实现长期同种异体移植物存活，而不需要慢性 免疫抑制 在本P01中，我们将通过借鉴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）了解训练免疫在肾移植中的临床相关性，ii）阐明机制， 训练的免疫力被诱导并导致器官排斥，以及iii）开发生物工程解决方案， 诊断和治疗性调节移植中的训练免疫。 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 以更有效地防止排斥并潜在地实现免疫耐受。如果成功，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。

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.