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 肾移植耐受性已在非人灵长类动物（NHP）和人类中实现， 非清髓性预处理和供者骨髓移植导致暂时性混合造血 嵌合体然而，相同的方案未能诱导耐受NHP心脏受体。的原因 这种免疫学上的二分法是未知的，但阐明其潜在机制可能会为新的策略提供信息。 以实现耐受性同种异体移植物的耐受性（目的1）。尽管心脏移植会造成免疫屏障， 最近开发了一种新的方案，首次诱导了完全MHC的长期耐受性， 在食蟹猴中进行不匹配的心脏移植。我们通过结合一种 与供体肾共移植的瞬时混合嵌合体方案。捐赠肾脏的出现 与减少炎症和增强宿主调节机制相关。自从牺牲一个肾脏 单纯的同种异体移植在人类心脏接受者中获得耐受性是站不住脚的，我们现在寻求一种有效的替代物 用于肾共移植（Aim 2）。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显示出与训练的巨噬细胞的功能状态相关的不同的表观遗传特征， 免疫力训练的免疫已被确定为事实上的先天免疫记忆，其特征在于代谢性免疫应答。 和先天免疫细胞的表观遗传变化，导致它们的高反应性。训练的巨噬细胞 炎症细胞因子反应增强，共刺激分子上调， 从而诱导更有效的适应性免疫应答。重要的是，我们的团队设计了一种骨髓 细胞特异性纳米免疫疗法，选择性抑制训练的免疫力，同时促进调节 机制，并实现了长期的心脏移植存活在小鼠和最近，在猴子。 基于这些发现，我们推测：1）训练的免疫有助于心脏耐受性抵抗 与肾脏同种异体移植物相比，2）经过训练的免疫抑制纳米疗法将产生抗炎/促炎作用， 调节环境，这将促进心脏耐受，而不需要肾脏共移植。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补充性的，在- 对心脏和肾脏接受者的训练免疫进行深入的机制分析， 免疫抑制靶点（由Core B开发）值得在NHP中进行测试。核心C将提供最先进的 分子测定和专业知识，以确定机制1）如何诱导训练免疫，2）作用 训练的免疫力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）我们的治疗方法如何 影响训练免疫力。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，以防止排斥反应，更有效地实现免疫耐受。如果 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， 改变骨髓移植和自身免疫性疾病的领域。