Studying and regulating trained immunity in mouse transplant models

研究和调节小鼠移植模型中训练有素的免疫力

• 批准号: 10642597
• 负责人: Abraham Teunissen
• 金额: $ 85.08万
• 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/10642597
• 关键词: Acute; Allograft Tolerance; Allografting; Animal Experiments; Animals; Automobile Driving; Bone Marrow; C57BL/6 Mouse; Cells; Chronic; Data; Dose; Epigenetic Process; FRAP1 gene; Family suidae; Genetic; Goals; Graft Rejection; Graft Survival; Heart; Heart Transplantation; Hematopoietic stem cells; Human; Image; Immune; Immune Tolerance; Immune response; Immune system; Immunity; ImmunoPET; Immunologic Memory; Immunologics; Immunosuppression; Kidney; Kidney Transplantation; Knock-out; Knockout Mice; Libraries; Longitudinal Studies; Mediating; Metabolic; Metabolism; Modeling; Modification; Monitor; Morbidity - disease rate; Mus; Myeloid Cells; Organ; Organ Transplantation; Organ failure; Pathway interactions; Patients; Play; Positron-Emission Tomography; Predisposition; Production; Rattus; Reperfusion Injury; Research Personnel; Resistance; Role; Stimulus; System; Testing; Therapeutic; Therapeutic immunosuppression; Training; Transplantation; Treatment Efficacy; allograft rejection; allotransplant; biomaterial compatibility; clinically relevant; design; epigenome; experimental study; heart allograft; immune activation; in vivo; inhibitor; innovation; insight; isoimmunity; kidney allograft; liver allograft; lung allograft; mouse model; multiple omics; nanobiologic; nanotherapeutic; nanotherapy; new therapeutic target; nonhuman primate; post-transplant; preservation; side effect; stem; success; transcriptome; transplant model

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.

摘要-项目2 器官移植彻底改变了器官衰竭患者的生活。然而，相关的 免疫抑制疗法引起显著的副作用并显示出次优的成功率。实现 在无慢性免疫抑制情况下，手术耐受状态将导致无限期的移植物存活， 相关的发病率。P01的研究人员揭示了在 耐受性诱导，跨物种保存。例如，肾脏和肝脏移植物更容易耐受 心脏和肺的同种异体移植此外，共同移植肾脏可促进心脏移植物的耐受性。这些 这种现象表明，调节同种异体移植物耐受性的机制未得到充分重视， 在治疗上，它可以将“耐受性抵抗”器官转变为“耐受性倾向”器官。 P01的研究者还证明了训练的免疫力在同种异体移植中起着关键作用。 排斥反应训练免疫是一种长期（>几个月）增强的先天免疫系统的功能性反应。 免疫细胞通过表观遗传机制在骨中造血祖细胞水平介导 骨髓，导致高反应性骨髓细胞的产生增强。我们证明了 移植诱导训练的免疫，并且随后的"训练的"骨髓细胞促进移植排斥。 项目2的前提是：1）器官对急性排斥反应敏感性的差异源于 训练免疫的不同程度或模式，以及2）治疗性抑制 移植后早期训练的免疫力将延长移植物存活。为此，我们制定了 本发明涉及骨髓亲合纳米治疗剂，其抑制训练的免疫调节剂mTOR并有效促进 移植物存活率无持续免疫抑制治疗。 在这里，我们建议在小鼠移植模型中研究和治疗性抑制训练的免疫力。要求1 将纵向评估对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成像和离体（多组学）分析。我们将努力最大化 使用相关敲除模型和同基因对照获得的机制见解。与此同时，目标2将 治疗性抑制训练免疫相关代谢和表观遗传途径，并类似地研究 对免疫系统和移植物存活的影响 本项目将揭示移植诱导训练免疫的机制及其在移植中的作用 排斥反应此外，它将推进一种基于训练免疫调节的创新治疗模式， 纳米生物制剂，并启动基于免疫PET成像的训练免疫的临床相关读数。 由Teunissen博士领导的项目2将通过提供机械见解和 验证新的治疗靶点。