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.

ISNAPSE摘要 根据临床，生化和组织学 标准在宿主免疫系统和同种异体移植物之间具有和谐平​​衡。减少 免疫抑制是挑战，对于某些但不是全部而言，会导致同种免疫激活，这可能导致 移植损伤。以前，我们已经证明了使用下一代对炎症负荷进行客观定量 病理技术可以有意义地区分标准组织学看起来正常的同种异体移植物 评估。各种炎症细胞的密度基本上将同种异体移植映射到同种异体反应性谱系上 从静止延伸到激活。在炎症指标中，免疫突触的密度， 定义为基于位置的淋巴细胞近端并与抗原呈递细胞相互作用 形态计量学和分子参数是那些可以承受挑战的人的最佳预测指标 免疫抑制剂量减少以完全停止。这些数据表明，在显然 静态同种异体移植物，肝内微环境，由免疫细胞及其细胞到细胞组成 相互作用，确定在IS时保持静止或屈服于激活的可能性 减少。我们的主要假设是肝内免疫之间相互作用的数量和性质 静止的细胞构成同种异体免疫原性的基础，是的关键决定因素 结果，当静止挑战时。 为了检验这一假设，Isynapse提出了以下特定目的：1）进行多中心单臂 对钙调蛋白抑制剂单一疗法的稳定儿童稳定儿童的试验。免疫抑制 将减少50％，从两次增加到一次。这种干预提供了直接的利益前景 减少药物暴露并简化给药。 2）确定肝内免疫细胞如何 网络调节基线和免疫抑制减少后的同种异体移植免疫原性。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。 对这两个数据流的迭代分析将充分清单构成的免疫细胞子集 肝微环境并阐明细胞间相互作用对维持或损失的影响 挑战时静止。 3）确定肝内细胞间相互作用的性质是否预测 循环中供体特异性的体液和细胞反应的变化。 肝移植提供了独特的环境，可以安全地研究宿主并在平衡时响应宿主 通过免疫抑制实现的挑战是挑战。了解同种异体移植方式的这些基本机制 在压力时保持或丢失静止对于在过度之间的危险平衡至关重要 以及免疫抑制，这转化为患者或移植物的次优结果。