Studying and regulating trained immunity in mouse transplant models

摘要--项目2 器官移植彻底改变了器官衰竭患者的生活。但是，关联的 免疫抑制疗法会产生严重的副作用，并显示出不理想的成功率。实现 手术耐受状态将导致无慢性免疫抑制的移植物无限期存活及其 相关发病率。这一P01‘S调查人员揭示了在器官特异性方面的显著差异 耐受性诱导，跨物种保存。例如，肾和肝移植更容易耐受。 而不是同种异体心脏和肺移植。此外，联合移植肾脏可提高心脏移植的耐受性。这些 现象表明，调节同种异体移植耐受的机制被低估，这可能是 通过治疗手段将“耐受”器官转变为“易耐受”器官。 S的研究人员也证明了训练有素的免疫在同种异体移植中起着关键作用 拒绝。训练有素的免疫是一种长期(&gt；几个月)增强的天然免疫功能反应 骨造血祖细胞水平的表观遗传机制介导的免疫细胞 骨髓，导致高反应性髓系细胞的产生增强。我们证明了这一点 移植诱导训练有素的免疫，随后的“训练有素”的髓系细胞促进移植物排斥反应。 项目2：S的前提是：1)器官对急性排斥反应的易感性差异源于 训练免疫训练的不同程度或方式；2)治疗抑制 移植后早期训练的免疫力将延长移植物的存活时间。与此相一致，我们开发了 抑制训练有素的免疫调节器mTOR并有效促进 未经持续免疫抑制治疗的同种异体移植物存活。 在这里，我们建议研究和治疗抑制小鼠移植模型中的训练性免疫。目标1 是否会纵向评估排斥心脏和自发接受肾脏的(先天)免疫反应 移植，使用体内免疫-PET成像和体外(多组学)分析。我们将努力最大限度地 使用相关的基因敲除模型和同基因对照获得的机制洞察力。同时，目标2将 治疗性地抑制训练免疫相关的代谢和表观遗传途径，并类似地研究其影响 对免疫系统和移植物存活率的影响。 该项目将揭示移植诱导训练性免疫背后的机制及其在移植物中的作用 拒绝。此外，它还将推进一种基于训练有素的免疫调节的创新治疗模式 纳米生物，并启动基于免疫-PET成像的训练有素免疫的临床相关读数。 由特尼森博士领导的项目2将通过提供机械性的见解和 验证新的治疗靶点。

SUMMARY – PROJECT 2 Transplantation has revolutionized the lives of patients suffering from organ failure. However, the associated immunosuppressive therapies induce significant side effects and display suboptimal success rates. Achieving a state of operational tolerance would lead to indefinite graft survival without chronic immunosuppression and its associated morbidity. This P01’s investigators have revealed pronounced organ-specific differences in tolerance induction, preserved across species. For example, kidney and liver allografts are easier to tolerize than heart and lung allografts. Moreover, co-transplanting a kidney promotes tolerance of heart allografts. These phenomena indicate an underappreciated mechanism regulating allograft tolerance, which might be therapeutically leveraged to turn “tolerant resistant” into “tolerance prone” organs. This P01’s investigators have also demonstrated that trained immunity plays a critical role in allograft rejection. Trained immunity is a long-term (>several months) increased functional responsiveness of innate immune cells mediated through epigenetic mechanisms at the level of hematopoietic progenitors in the bone marrow, resulting in enhanced production of hyperresponsive myeloid cells. We demonstrated that transplantation induces trained immunity and that the ensuing ‘trained’ myeloid cells promote graft rejection. Project 2’s premise is 1) that the difference between organs’ susceptibility to acute rejection stems from different degrees or modes of trained immunity of trained immunity and that 2) therapeutically inhibiting trained immunity early post-transplantation will prolong graft survival. In line with this, we have developed bone marrow-avid nanotherapeutics which inhibit the trained immunity regulator mTOR and effectively promote allograft survival without continuous immunosuppressive therapy. Here, we propose studying and therapeutically inhibiting trained immunity in mouse transplant models. Aim 1 will longitudinally assess the (innate) immune response to rejecting heart and spontaneously accepting kidney transplantation, using in vivo immuno-PET imaging and ex vivo (multi-omics) analyses. We will strive to maximize the obtained mechanistic insights using relevant knockout models and syngeneic controls. In parallel, Aim 2 will therapeutically inhibit trained immunity-related metabolic and epigenetic pathways and similarly study the effects on the immune system and graft survival. This Project will unravel the mechanisms behind transplantation-induced trained immunity and its role in graft rejection. Furthermore, it will advance an innovative treatment paradigm based on trained immunity-regulating nanobiologics and initiate clinically relevant readouts of trained immunity based on immuno-PET imaging. Project 2, led by Dr. Teunissen, will interface with Projects 1 and 3 by providing mechanistic insights and validating novel therapeutic targets.