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 移植彻底改变了器官衰竭患者的生活，但随之而来的问题也随之而来。 免疫抑制疗法会引起显着的副作用并显示出次优的成功率。 如果没有长期免疫抑制，操作耐受状态将导致移植物无限期存活。 P01 的研究人员揭示了相关的发病率的明显器官特异性差异。 耐受诱导，跨物种保存，例如，肾脏和肝脏同种异体移植物更容易耐受。 与心脏和肺同种异体移植相比，联合移植肾脏可促进心脏同种异体移植的耐受性。 现象表明调节同种异体移植物耐受性的机制未被充分认识，这可能是 通过治疗手段将“耐受性抵抗”器官转变为“耐受性倾向”器官。 这个 P01 的研究人员还证明，训练有素的免疫力在同种异体移植中发挥着关键作用 训练有素的免疫力是一种长期（>几个月）增强的先天功能反应能力。 通过骨中造血祖细胞水平的表观遗传机制介导的免疫细胞 骨髓，导致高反应性骨髓细胞的产生增加，我们证明了这一点。 移植会诱导经过训练的免疫力，随后“经过训练的”骨髓细胞会促进移植物排斥。 项目2的前提是1）器官对急性排斥反应的易感性差异源于 训练有素的免疫的不同程度或模式以及2)治疗性抑制 移植后早期训练有素的免疫力将延长移植物的存活时间。 骨髓热纳米疗法可抑制经过训练的免疫调节剂 mTOR 并有效促进 无需持续免疫抑制治疗的同种异体移植物存活率。 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有素的免疫力。 将纵向评估对排斥心脏和自发接受肾脏的（先天）免疫反应 我们将努力最大限度地利用体内免疫 PET 成像和离体（多组学）分析。 同时，Aim 2 将使用相关的敲除模型和同基因对照获得机械见解。 抑制经过训练的免疫相关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的影响。 该项目将揭示移植诱导的训练免疫背后的机制及其在移植中的作用 此外，它将推进基于训练有素的免疫调节的创新治疗模式。 纳米生物制剂，并根据免疫 PET 成像启动经过训练的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。