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 移植彻底改变了患有器官衰竭的患者的生活。但是，关联 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。实现 操作耐受状态将导致无慢性免疫抑制及其 相关的发病率。该P01的调查人员揭示了明显的器官特异性差异 耐受性诱导，保留在物种之间。例如，肾脏和肝脏同种异体移植物更容易耐受 比心脏和肺同种异体移植。此外，共同移植肾脏会促进心脏同种异体移植的耐受性。这些 现象表明一种调节同种异体耐受性的机制不足，这可能是 在治疗上杠杆化将“耐受性”转化为“容耐力”的器官。 该P01的调查人员还表明，受过训练的免疫学在分类中起着至关重要的作用 拒绝。训练有素的免疫力是长期（>几个月）先天的功能响应性提高 免疫细胞通过骨骼中造血祖细胞水平的表观遗传机制介导的免疫细胞 骨髓，导致高反应性髓样细胞的产生增强。我们证明了这一点 移植会诱导受过训练的免疫力，并确保“训练”的髓样细胞促进移植物排斥。 项目2的前提是1）器官对急性拒绝步骤的敏感性之间的差异 不同程度或受过训练的免疫史的模式和2）治疗抑制 受过训练的免疫力早期移植将延长移植物的存活。与此相符，我们已经开发了 骨髓 - avid纳米疗法抑制训练训练的免疫调节剂MTOR并有效促进 同种异体移植生存期，没有连续的免疫抑制治疗。 在这里，我们建议在小鼠移植模型中研究和热抑制受过训练的免疫功能。目标1 将纵向评估（先天性的）免疫反应，以拒绝心脏和赞助肾脏 使用体内免疫-PET成像和体内（多词）分析的移植。我们将努力最大化 使用相关的敲除模型和同步控制获得的机械见解。同时，AIM 2将 治疗抑制训练训练的免疫学相关的代谢和表观遗传途径，并类似地研究了影响 在免疫系统和移植物存活下。 该项目将揭示移植引起的受过训练的免疫力及其在移植中的作用的机制 拒绝。此外，它将基于受过训练的免疫调节的创新治疗范例 纳米生物学并启动基于免疫PET成像的受过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 验证新颖的治疗靶标。