iSYNAPSE: Early signals of the transition from immune quiescence to activation in the liver allograft microenvironment and in the circulation

iSYNAPSE：肝脏同种异体移植物微环境和循环中从免疫静止过渡到激活的早期信号

• 批准号: 10622220
• 负责人: Sandy Feng
• 金额: $ 27.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622220
• 关键词: Acute; Allografting; Antigen-Presenting Cells; Antigens; B-Cell Development; B-Lymphocytes; Biochemical; Biopsy; Buffers; Calcineurin inhibitor; Cell Communication; Cell physiology; Cells; Child; Childhood; Chronic; Circulation; Clinical; Clinical Trials; Complex; Data; Data Correlations; Dendritic Cells; Development; Discontinuous Capillary; Docking; Dose; Endothelial Cells; Equilibrium; Equipment and supply inventories; Evaluation; Goals; Grant; Histologic; Histopathology; Immune; Immune response; Immune system; Immunohistochemistry; Immunologics; Immunoprecipitation; Immunosuppression; Inflammatory; Injury; Intervention; Kupffer Cells; Liver; Lymphocyte; Lymphocyte antigen; Maintenance; Maps; Molecular; Nature; Organ Transplantation; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Platelet aggregation; Process; Safety; Signal Transduction; Solid; Stress; Synapses; System; T memory cell; T-Lymphocyte; Tacrolimus; Techniques; Testing; Tissues; Translating; Transplant Recipients; arm; automated image analysis; cell type; data streams; density; digital; effector T cell; efficacy evaluation; graft function; immune activation; immunogenicity; immunological synapse; insight; intrahepatic; liver allograft; liver transplantation; next generation; response; transcriptome; transcriptomics; whole slide imaging

iSYNAPSE Summary Children with liver transplants with excellent graft function according to clinical, biochemical, and histological criteria enjoy a harmonious equilibrium between the host immune system and the allograft. Reducing immunosuppression is challenge that, for some but not all, precipitates alloimmune activation that can result in graft injury. Previously, we have shown that objective quantification of inflammatory load using next generation pathology techniques can meaningfully differentiate allografts that appear normal by standard histological evaluation. The density of various inflammatory cells essentially maps allografts onto an alloreactivity spectrum that extends from quiescent to activated. Among inflammatory metrics, the density of immunologic synapses, defined as a lymphocyte proximal to and interacting with an antigen-presenting cell based on positional, morphometric, and molecular parameters, was the best predictor of those who could withstand the challenge of immunosuppression dose reduction to complete cessation. These data suggest that, within an apparently quiescent allograft, the intrahepatic microenvironment, comprised of immune cells and their cell-to-cell interactions, determines the likelihood of maintaining quiescence or succumbing to activation when IS is reduced. Our primary hypothesis is that the number and nature of interactions between intrahepatic immune cells at quiescence constitutes the basis of liver allograft immunogenicity and is the key determinant of outcome, when quiescence is challenged. To test this hypothesis, iSYNAPSE proposes the following specific aims: 1) Conduct a multicenter, single-arm trial for stable children with healthy liver allografts on calcineurin inhibitor monotherapy. Immunosuppression will be reduced by 50%, from twice to once daily dosing. This intervention offers direct prospect of benefit by reducing medication exposure and simplifying administration. 2) Determine how intrahepatic immune cell networks regulate liver allograft immunogenicity at baseline and following immunosuppression reduction. Using next generation pathology and single cell transcriptomics, we will characterize the phenotype and the transcriptome of the lymphocytes and the antigen-presenting cells participating in immunological synapses. The iterative analyses of these two data streams will fully inventory the immune cell subsets that comprise the liver microenvironment and elucidate the impact of cell-to-cell interactions on the maintenance or loss of quiescence when challenged. 3) Ascertain whether the nature of intrahepatic cell-to-cell interactions predict changes in donor-specific humoral and cellular responses in the circulation. Liver transplantation provides a unique context to safely study the host and graft respond when the equilibrium achieved by immunosuppression is challenged. Understanding these basic mechanisms of how allograft quiescence is maintained or lost when stressed is essential to navigate the treacherous balance between over- and under-immunosuppression that translate into suboptimal outcomes for either the patient or the graft.

iSYNAPSE摘要 根据临床、生化和组织学，肝移植儿童具有良好的移植功能 标准在宿主免疫系统和同种异体移植物之间享有和谐的平衡。减少 免疫抑制是一个挑战，对于一些但不是全部，它会沉淀同种免疫激活， 移植物损伤以前，我们已经表明，使用下一代炎症负荷的客观定量 病理学技术可以有意义地区分标准组织学检查显示正常的同种异体移植物， 评价各种炎症细胞的密度基本上将同种异体移植物映射到同种异体反应谱上 从静止状态到激活状态在炎症指标中，免疫突触的密度， 定义为接近抗原呈递细胞并基于位置与抗原呈递细胞相互作用的淋巴细胞， 形态学和分子参数，是那些能够经受住挑战的人的最佳预测指标。 减少免疫抑制剂量至完全停止。这些数据表明，在明显的范围内， 静止的同种异体移植物，即肝内微环境，由免疫细胞及其细胞间 相互作用，决定了维持静止或屈服于激活的可能性时，是 降低我们的主要假设是，肝内免疫系统之间相互作用的数量和性质 处于静止状态的细胞构成了肝移植免疫原性的基础，并且是肝移植免疫原性的关键决定因素。 结果，当平静受到挑战时。 为了验证这一假设，iSYNAPSE提出了以下具体目标：1）进行一项多中心、单组 钙调磷酸酶抑制剂单药治疗健康肝移植稳定儿童的试验。免疫抑制 将减少50%，从每日两次给药减少到每日一次给药。这种干预提供了直接的受益前景， 减少药物暴露并简化给药。2)确定肝内免疫细胞 在基线和免疫抑制减少后，免疫网络调节肝移植免疫原性。使用 下一代病理学和单细胞转录组学，我们将表征表型和 参与免疫突触的淋巴细胞和抗原呈递细胞的转录组。 这两个数据流的迭代分析将完全清点构成免疫细胞亚群的免疫细胞亚群。 肝脏微环境，并阐明细胞间相互作用对维持或丧失 在受到挑战时保持沉默。3)确定肝内细胞间相互作用的性质是否预测 循环中供体特异性体液和细胞反应的变化。 肝移植提供了一个独特的背景下，安全地研究宿主和移植物的反应时，平衡 免疫抑制的效果受到了挑战。了解同种异体移植物 平静是保持或失去压力时，是必不可少的导航之间的危险平衡过度， 以及免疫抑制不足，这转化为患者或移植物的次优结果。