Using trained immunity-inhibiting nanobiologics to achieve tolerance of heart allografts in non-human primates

使用经过训练的免疫抑制纳米生物制剂来实现非人类灵长类动物同种异体心脏移植的耐受性

• 批准号: 10642598
• 负责人: Joren C Madsen
• 金额: $ 91.99万
• 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/10642598
• 关键词: Affect; Allograft Tolerance; Allografting; Anti-Inflammatory Agents; Autoimmune Diseases; Automobile Driving; B-Lymphocytes; Biological Assay; Bone Marrow; Bone Marrow Diseases; Bone Marrow Transplantation; Cells; Chimerism; Chronic; Collaborations; Epigenetic Process; Exhibits; Funding; Graft Survival; Graft Tolerance; Heart; Hematopoietic; Hematopoietic stem cells; Human; Immune; Immune Tolerance; Immunity; Immunologic Memory; Immunologics; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response Pathway; Kidney; Kidney Transplantation; Laboratories; Lipoproteins; Liver; Lung; Macaca fascicularis; Macrophage; Metabolic; Modeling; Modification; Molecular; Monkeys; Morbidity - disease rate; Mus; Myeloid Cells; Nanoimmunotherapy; Nature; Organ; Organ Transplantation; Play; Prodrugs; Protocols documentation; Reporting; Resistance; Role; Sirolimus; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Training; Transplant-Related Disorder; Transplantation; adaptive immune response; adaptive immunity; comparison control; conditioning; design; heart allograft; innovation; insight; kidney allograft; lipophilicity; mTOR Inhibitor; mTOR inhibition; mortality; nanobiologic; nanomaterials; nanotherapeutic; nanotherapy; nonhuman primate; novel; pathogen; post-transplant; prevent; response

SUMMARY – PROJECT 3 Kidney allograft tolerance has been achieved in nonhuman primates (NHPs) and humans by combining nonmyeloablative conditioning and donor bone marrow transplantation resulting in transient mixed hematopoietic chimerism. However, identical protocols have failed to induce tolerance in NHP heart recipients. The reason for this immunological dichotomy is unknown but elucidating its underlying mechanisms could inform new strategies for achieving tolerance of resistant allografts (Aim 1). Despite the immune barriers posed by heart allografts, we have recently developed a novel protocol that has, for the first time, induced long-term tolerance of fully MHC mismatched heart allografts in cynomolgus monkeys. We attained this remarkable result by combining a transient mixed chimerism protocol with donor kidney co-transplantation. The presence of the donor kidney was associated with diminished inflammation and enhanced host regulatory mechanisms. Since sacrificing a kidney allograft simply to achieve tolerance in human heart recipients is untenable, we now seek an effective substitute for kidney co-transplantation (Aim 2). Recently, our team reported that following organ transplantation, macrophages in the allograft display distinct epigenetic signatures associated with the functional state of trained immunity. Trained immunity has been identified as de facto innate immune memory characterized by metabolic and epigenetic changes in innate immune cells, resulting in their hyperresponsiveness. Trained macrophages have heightened inflammatory cytokine responses and upregulated costimulatory molecules, which consequently induce more potent adaptive immune responses. Importantly, our team has designed a myeloid cell-specific nanoimmunotherapy that selectively inhibits trained immunity while promoting regulatory mechanisms and has achieved long-term cardiac allograft survival in mice and, more recently, in monkeys. Based on these findings, we hypothesize that 1) trained immunity contributes to the tolerance resistance of heart versus kidney allografts, and 2) trained immunity-inhibiting nanotherapy will generate an anti-inflammatory/pro- regulatory milieu that will facilitate heart tolerance without the need for kidney co-transplantation. We will test these hypotheses in Project 3. Murine studies in Project 2 will guide Project 3 by providing complementary, in- depth mechanistic analyses of trained immunity in heart and kidney recipients and also identifying new trained immunity-inhibiting targets (developed by Core B) worthy of testing in NHPs. Core C will provide state-of-the-art molecular assays and expertise, to determine mechanistically 1) how trained immunity is induced, 2) the role trained immunity plays in the organ-specific differences observed in tolerance induction, and 3) how our therapies impact trained immunity. We anticipate that together, these highly interactive Projects will generate new and innovative therapeutic strategies to prevent rejection and more effectively achieve immune tolerance. If successful, these studies could impact the entire field of transplantation and provide insights that could also be field-changing for bone marrow transplantation and autoimmune disease.

摘要 - 项目3 通过组合，在非人类灵长类动物（NHP）和人类中实现了肾脏同种异体耐受性 非乳不公动调节和供体骨髓移植，导致短暂的混合造血 嵌合体。但是，相同的方案未能引起NHP心脏受体的耐受性。原因 这种免疫二分法尚不清楚，但阐明其潜在机制可以为新策略提供信息 为了实现耐药合金的耐受性（AIM 1）。尽管心脏合金构成的免疫障碍，我们 最近开发了一种新的方案，该方案首次引起了完全MHC的长期公差 在雌雄同体中，心脏不匹配的心脏同种异体移植。我们结合了 瞬态混合嵌合方案与供体肾脏共转移。供体肾脏的存在是 与感染减少和增强的宿主调节机制有关。自从牺牲肾脏以来 同种异体移植仅仅是为了实现人心的接受者的宽容是站不住脚的，我们现在寻求有效的替代品 用于肾脏的转移（AIM 2）。最近，我们的团队报告说，随着器官移植， 同种异体移植物中的巨噬细胞显示出与受过训练的功能状态相关的不同表观遗传特征 免疫。训练有素的免疫力已被确定为事实上的先天免疫记忆，其特征是代谢 和先天免疫小球的表观遗传变化，从而导致其过度反应。训练有素的巨噬细胞 炎性细胞因子反应增强和更新的共刺激分子，这些分子已增加 因此，诱导了更多潜在的适应性免疫复杂。重要的是，我们的团队设计了一个髓样 细胞特异性的纳米免疫疗法，可有选择地抑制受过训练的免疫学，同时促进调节性 机制并已在小鼠中以及最近在猴子中实现了长期心脏同类生存。 根据这些发现，我们假设1）受过训练的免疫功能有助于心脏的耐受性 相对于肾脏同类，2）受过训练的免疫纳米疗法将产生抗炎/促疾病 监管环境将促进心脏耐受性，而无需肾脏共同进行。我们将测试 项目3中的这些假设。项目2中的鼠类研究将通过提供完整性，IN-将指导项目3 心脏和Kidsney接收者的训练有素的免疫力的深度机械分析，还确定了新训练的 抑制免疫力的靶标（由核心B开发）值得在NHP中进行测试。核心C将提供最新的 分子测定和专业知识，以机械的方式确定1）如何诱导训练的免疫学，2） 受过训练的免疫功能在耐受性诱导中观察到的器官特异性差异中，以及3）我们的疗法如何 影响训练有素的免疫力。我们预计，这些高度互动的项目将共同产生新的和 创新的治疗策略，以防止排斥和更有效地实现免疫耐受性。如果 成功，这些研究可能会影响整个移植领域，并提供可能是 骨髓移植和自身免疫性疾病的野外改变。