Apoptotic Donor Leukocytes to Promote Kidney Transplant Tolerance

凋亡供体白细胞促进肾移植耐受

• 批准号: 10622209
• 负责人: Bernhard Josef Hering
• 金额: $ 97.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622209
• 关键词: Acute; Alleles; Allografting; Antigens; Apoptosis; Apoptotic; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Data; Frequencies; Generations; Graft Survival; Immune; Immunosuppression; Immunotherapy; Inflammasome; Infusion procedures; Interleukin-10; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Leukocytes; Lymphoid Cell; Macaca; Macaca fascicularis; Macaca mulatta; Memory; Modeling; Modification; Monoclonal Antibodies; Morbidity - disease rate; Myeloid Cells; Organ; Organ Transplantation; Pathogenicity; Peptides; Phenotype; Pre-Clinical Model; Process; Protocols documentation; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Rodent; Sirolimus; Solid; Sorting; Specificity; Spleen; Study models; System; T-Lymphocyte; TNFRSF5 gene; Testing; Thymus Gland; Translations; Transplantation; Transplantation Tolerance; Urine; Work; antagonist; clinical translation; efficacy evaluation; efficacy study; exhaust; exhaustion; high dimensionality; immunoregulation; improved; islet; islet allograft; kidney allograft; living kidney donor; migration; nonhuman primate; peptide I; prevent; programmed cell death ligand 1; programs; recruit; single cell sequencing; synergism; transplant model

PROJECT 2 SUMMARY We demonstrated that two peritransplant infusions of apoptotic donor leukocytes (ADLs) and transient immunosuppression (TIS) with α-CD40, rapamycin, sTNFR, and α-IL-6R induced long-term (>1 year) tolerance to islet allografts in 5 of 5 nonsensitized, 1 MHC-II DRB allele-matched nonhuman primates (NHPs). Project 2 will examine the efficacy and mechanisms of the ADL+TIS regimen in a kidney transplant model and apply high- dimensional immune profiling to guide protocol refinements, with the PRINCIPAL OBJECTIVE of developing a safe, effective, and clinically translatable protocol for inducing stable tolerance in living donor kidney transplantation. WE HYPOTHESIZE that the ADL+TIS regimen, with modifications deemed necessary to facilitate successful translation to a solid organ transplant setting and with refinements informed by results of the overall U19 program, promotes long-term graft survival in living donor kidney transplant models in NHPs through operational tolerance. To test this hypothesis and facilitate the clinical translation of ADL+TIS, we propose two SPECIFIC AIMS: AIM #1: To determine the efficacy and mechanisms of ADL infusions combined with transient immunosuppression in inducing and maintaining tolerance in a NHP renal transplant model Studies determining the efficacy of the ADL+TIS protocol in achieving operational tolerance of renal allografts in NHPs will be accompanied by deep immune profiling of blood, graft, spleen, and urine to investigate the effects of the protocol on the abundance and activation profiles of distinct effector, exhausted, and regulatory immune cell subsets in various compartments and their spatial organization within graft and spleen. AIM #2: To study the efficacy and mechanisms of inflammasome inhibition and IL-1b antagonism to promote renal transplant tolerance induced by ADL infusions and transient immunosuppression in NHPs Studies in this Aim will determine the ability of strategies inhibiting the inflammasome and its products to synergize with ADL+TIS in promoting operational tolerance in a renal transplant model in NHPs. Mechanistic studies will investigate how inflammasome inhibition and IL-1b antagonism modify the effects of ADLs + TIS on frequencies and activation profiles of myeloid and lymphoid cell subsets in blood, urine, and spleen and their recruitment to and spatial interaction within coordinated immune regulation domains in the renal allograft. The SIGNIFICANCE & INNOVATION of the proposal lie in the efficacy of the ADL+TIS protocol to deplete and exhaust allospecific T cells and to create potent immune regulation. The prospects for tolerance induction to renal transplants in NHPs are high, based on documented tolerance to renal transplants in rodents and islet transplants in NHPs and opportunities for rational refinements of the strategy created by system-level immune profiling.

项目2摘要 我们证明了凋亡供体白细胞（ADL）和瞬态的两种腹腔内植物输注 具有α-CD40，雷帕霉素，STNFR和α-IL-6R的免疫抑制（TIS）诱导长期（> 1年）耐受性 在5个非敏化的1个MHC-II DRB等位基因匹配的非人类灵长类动物（NHP）中的5个中的5个中的胰岛包围。项目2 将检查ADL+TIS方案在肾脏移植模型中的效率和机制，并应用高 尺寸免疫分析以指导协议修补，其主要目的是开发安全， 有效且可翻译的方案，可引起活供体肾移植中稳定的耐受性。 我们假设ADL+TIS方案，并认为有必要进行修改以促进成功 转化为固体器官移植设置，并通过整体U19计划的结果告知改进， 通过操作耐受性，可以在NHP中促进长期的移植物生存。 为了检验这一假设并促进ADL+TI的临床翻译，我们提出了两个具体的目的： 目的＃1：确定ADL输注的效率和机制与瞬态相结合 NHP肾移植模型中诱导和维持耐受性的免疫抑制 确定ADL+TIS方案在实现肾脏专辑中的效率的研究 NHP将伴随着血液，移植物，脾和尿液的深度免疫分析，以研究影响 关于不同效应子的抽象和激活曲线方案，疲惫和调节性免疫 各个隔室中的细胞子集及其在移植物和索伦中的空间组织。 目的＃2：研究炎性体抑制和IL-1B拮抗作用的效率和机制 促进由ADL输注诱导的肾移植耐受性和NHP中的瞬时免疫抑制 以此目的的研究将决定抑制炎症体及其产品的策略能力 与ADL+TI协同促进NHP中肾移植模型中的操作耐受性。机理 研究将研究炎性体抑制和IL-1B拮抗作用如何改变ADLS + TI对 血液，尿液和脾脏中髓样和淋巴样细胞亚群的频率和激活曲线及其 在肾脏外表源中协调的免疫调节域内募集和空间相互作用。 提案的意义和创新在于ADL+TIS协议的效率复制和排气 同种T细胞并创建潜在的免疫调节。容忍肾脏的前景 基于对啮齿动物和胰岛移植中肾移植的耐受性，NHP中的移植物很高 在NHP和机遇中，通过系统级免疫分析创建的策略进行理性改进。