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 通过结合以下方法，非人灵长类动物 (NHP) 和人类已实现肾同种异体移植耐受 非清髓性调理和供体骨髓移植导致短暂的混合造血 然而，相同的方案未能在 NHP 心脏接受者中诱导耐受。 这种免疫学二分法尚不清楚，但阐明其潜在机制可以为新策略提供信息 为了实现耐药同种异体移植物的耐受性（目标 1），尽管同种异体心脏移植物造成了免疫障碍，但我们 最近开发了一种新方案，首次诱导了完全 MHC 的长期耐受 我们通过结合食蟹猴的不匹配同种异体心脏移植获得了这一显着结果。 与供体肾共移植的瞬时混合嵌合方案 供体肾的存在是。 自从牺牲肾脏后，与减少炎症和增强宿主调节机制有关。 同种异体移植仅仅为了在人类心脏接受者中实现耐受性是站不住脚的，我们现在寻求一种有效的替代品 最近，我们的团队报告说，在器官移植后， 同种异体移植物中的巨噬细胞表现出与受过训练的功能状态相关的独特表观遗传特征 训练有素的免疫已被认为是事实上的先天免疫记忆，其特征是代谢。 先天免疫细胞的表观遗传变化，导致巨噬细胞过度反应。 具有炎症细胞因子反应和上调的共刺激分子， 从而诱导更有效的适应性免疫反应。重要的是，我们的团队设计了一种骨髓细胞。 细胞特异性纳米免疫疗法，选择性抑制训练有素的免疫力，同时促进调节 机制，并已在小鼠和最近的猴子中实现了同种异体心脏移植物的长期存活。 基于这些发现，我们发现：1）训练有素的免疫力有助于心脏的耐受性 与肾同种异体移植相比，2）经过训练的免疫抑制纳米疗法将产生抗炎/促- 我们将测试将促进心脏耐受性而不需要肾脏联合移植的监管环境。 项目 3 中的这些假设。项目 2 中的小鼠研究将通过提供补充性的、in- 对心脏和肾脏受者的训练有素的免疫力进行深度机制分析，并确定新的训练有素的免疫力 值得在 NHP 中进行测试的免疫抑制靶点（由核心 B 开发）将提供最先进的技术。 分子检测和专业知识，从机制上确定 1) 如何诱导训练有素的免疫力，2) 作用 训练有素的免疫在耐受诱导中观察到的器官特异性差异中发挥作用，以及3）我们的疗法如何 我们预计，这些高度互动的项目将共同产生新的和 预防排斥反应并更有效地实现免疫耐受的创新治疗策略。 如果成功的话，这些研究可能会影响整个移植领域，并提供一些见解，也可以 骨髓移植和自身免疫性疾病领域的变革。