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 总结 我们证明了两次移植前后输注凋亡供体白细胞（ADL）和短暂输注 使用 α-CD40、雷帕霉素、sTNFR 和 α-IL-6R 进行免疫抑制 (TIS) 诱导长期（>1 年）耐受 5 个非致敏、1 个 MHC-II DRB 等位基因匹配的非人灵长类动物 (NHP) 中的 5 个进行胰岛同种异体移植，项目 2。 将检查 ADL+TIS 方案在肾移植模型中的功效和机制，并应用高 三维免疫分析来指导方案改进，其主要目标是开发一种安全、 用于在活体肾移植中诱导稳定耐受性的有效且可临床转化的方案。 我们假设 ADL+TIS 方案经过必要的修改以促进成功 转化为实体器官移植环境，并根据整个 U19 计划的结果进行改进， 通过操作耐受性促进 NHP 活体肾移植模型中移植物的长期存活。 为了检验这一假设并促进 ADL+TIS 的临床转化，我们提出了两个具体目标： 目标#1：确定 ADL 输注结合瞬时疗法的功效和机制 免疫抑制在 NHP 肾移植模型中诱导和维持耐受性 确定 ADL+TIS 方案在实现肾同种异体移植手术耐受性方面的功效的研究 NHP 将伴随血液、移植物、脾脏和尿液的深度免疫分析，以研究其效果 关于不同效应子、耗尽和调节免疫的丰度和激活概况的协议 不同区室中的细胞亚群及其在移植物和脾脏内的空间组织。 目标#2：研究炎症小体抑制和 IL-1b 拮抗作用的功效和机制 肾促进 ADL 输注和 NHP 短暂免疫抑制诱导的移植耐受 该目标的研究将确定抑制炎性体及其产物的策略的能力 与 ADL+TIS 协同促进 NHP 肾移植模型的操作耐受性。 研究将探讨炎症小体抑制和 IL-1b 拮抗作用如何改变 ADL + TIS 对 血液、尿液和脾脏中骨髓细胞和淋巴细胞亚群的频率和激活概况及其 同种异体肾移植物中协调免疫调节域的募集和空间相互作用。 该提案的意义和创新点在于ADL+TIS协议消耗和耗尽的功效 同种异体特异性 T 细胞并产生有效的免疫调节，诱导肾耐受。 根据啮齿类动物肾移植和胰岛移植的耐受性记录，NHP 的移植率很高 在 NHP 中，以及对系统级免疫分析所创建的策略进行合理改进的机会。