Cell-Mediated Antiretroviral Drug Transport in the Lymph Node

细胞介导的抗逆转录病毒药物在淋巴结中的转运

• 批准号: 10327086
• 负责人: Jason Paul Gleghorn
• 金额: $ 23.73万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327086
• 关键词: 3-Dimensional; Active Biological Transport; Anti-Retroviral Agents; Architecture; Area; Atazanavir; Blocking Antibodies; Blood; Blood Vessels; Cell Cycle Kinetics; Cell model; Cells; Clinical; Clinical Research; Computer Models; Data; Development; Diffusion; Disease; Drug Carriers; Drug Kinetics; Drug Transport; Drug usage; Exclusion; Exhibits; Experimental Designs; Extravasation; Future; Geometry; HIV; High Pressure Liquid Chromatography; Human; Image; Kinetics; Liquid substance; Lobule; Location; Lymph; Lymphatic; Lymphocyte; Lymphocyte Function; Lymphocyte Suppression; Lymphoid; Lymphoid Tissue; Macaca; Mediating; Modeling; Morbidity - disease rate; Mus; Pathway interactions; Patients; Pattern; Penetration; Pharmaceutical Preparations; Pharmacology; Physical therapy; Plasma; Play; Primates; Process; RNA; Regimen; Role; Sinus; Site; Tenofovir; Tissues; Variant; Virus Replication; antiretroviral therapy; clinical predictors; clinically significant; drug distribution; drug efficacy; in vivo; in vivo Model; innovation; laser capture microdissection; lipophilicity; lymph nodes; lymphocyte trafficking; migration; mortality; mouse model; novel therapeutics; particle; passive transport; pharmacokinetics and pharmacodynamics; physical property; predictive modeling; reconstruction; standard of care; therapeutic development; trafficking; virology

ABSTRACT Recent in vivo studies in humans and primates have demonstrated that the anti-retroviral drugs used to suppress HIV do not distribute uniformly into lymphatic tissues, and drugs that are present in the blood plasma may be completely absent from the lymph nodes of the same patients. The clinical significance of this finding is not well understood, but elevated levels of HIV virus in the lymph nodes of these patients suggest that this may act as a sanctuary site for viral replication. We hypothesize that the selective manner in which drugs and cells are transported into the lymph node from the blood and fluid lymph is the mechanism of exclusion, and that the precise 3D geometry of the lymph node can explain the variation in drug penetration between different lymph nodes, or even between different locations in the same lymph node. In addition to free drug transport patterns, intracellular drug concentration is another crucial factor in the heterogeneous drug distribution observed in the LN. Lymphocytes can act as drug carriers and shuttle drugs through the LN incidentally during trafficking. Cellular transport rates are an order of magnitude slower than free drug transport rates, so cell-mediated trafficking is not a major contributor to drug concentration in well-perfused tissues. In the LN, however, lymphocytes employ active transport mechanisms that allow them to pass the barriers described above, so transport by this pathway can significantly change the overall dynamics of drug concentration. In aim one, we will develop and validate a scalable predictive model of drug transport into lymphoid lobules using 3D reconstructed murine lymph nodes. This model will be equipped with full vascular and sinus geometries and can be used to predict drug distributions in any lobule and determine transport rates. In aim 2, we will investigate the role lymphocytes play in overall drug concentration in the lobule by impeding lymphocyte entry via functional antibody blocking. We propose to integrate experimental design and computational modeling to better understand the mechanisms of drug exclusion from lymph nodes and guide the development of therapeutics that overcome them.

摘要 最近在人类和灵长类动物体内的研究表明，用于抑制 HIV并不均匀地分布到淋巴组织中，并且存在于血浆中的药物可能会被淋巴细胞吸收。 在相同患者的淋巴结中完全没有。这一发现的临床意义尚不明确 我们理解，但这些患者淋巴结中HIV病毒水平的升高表明，这可能是一种 病毒复制的避难所我们假设药物和细胞的选择性方式是 从血液和液体淋巴输送到淋巴结是排斥的机制， 淋巴结的精确3D几何形状可以解释不同淋巴结之间药物渗透的变化 淋巴结之间，甚至是同一淋巴结的不同位置之间。除了自由药物运输模式外， 细胞内药物浓度是在细胞内观察到的不均匀药物分布中的另一个关键因素。 LN.淋巴细胞可以作为药物载体，在运输过程中偶尔通过LN穿梭药物。蜂窝 转运速率比游离药物转运速率慢一个数量级，因此细胞介导的转运是 不是灌注良好组织中药物浓度的主要贡献者。然而，在LN中，淋巴细胞 主动运输机制，使他们能够通过上述障碍，因此运输通过这一途径 可以显著改变药物浓度的整体动力学。在目标一中，我们将开发和验证一个 使用3D重建的小鼠淋巴结的药物转运到淋巴小叶中的可扩展预测模型。 该模型将配备完整的血管和窦几何形状，可用于预测药物分布 并确定转运速率。在目标2中，我们将研究淋巴细胞在整体药物治疗中的作用。 通过功能性抗体阻断阻止淋巴细胞进入，从而在小叶中浓缩。我们建议 整合实验设计和计算建模，以更好地了解药物的作用机制 排除淋巴结，并指导治疗，克服他们的发展。