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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的最近在人类和灵长类动物的体内研究表明，用于抑制的抗逆转录病毒药物 HIV不一致地分布到淋巴组织中，血浆中存在的药物可能是完全没有同一患者的淋巴结。该发现的临床意义不佳理解，但这些患者淋巴结中的HIV病毒水平升高，这表明这可能充当病毒复制的保护区。我们假设药物和细胞的选择性方式从血液和液体淋巴传输到淋巴结中是排除机制，并且淋巴结的精确3D几何形状可以解释不同淋巴之间药物渗透的变化节点，甚至在同一淋巴结中的不同位置之间。除了免费的药物运输模式外，细胞内药物浓度是观察到的异质药物分布的另一个关键因素 Ln。淋巴细胞可以在贩运过程中偶然用作药物携带者和穿梭药物。细胞运输速率比游离药物运输速率慢，因此细胞介导的贩运是并不是吸毒浓度良好的组织的主要贡献者。然而，在LN中，淋巴细胞采用主动运输机制，使他们能够通过上述障碍，因此通过此途径运输可以显着改变药物浓度的整体动力学。在目标中，我们将开发和验证使用3D重建的鼠淋巴结将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在任何小叶中并确定运输速率。在AIM 2中，我们将研究淋巴细胞在整体药物中的作用通过功能抗体阻断阻碍淋巴细胞进入小叶中的浓度。我们建议整合实验设计和计算建模，以更好地了解药物的机制排除淋巴结，并指导克服它们的治疗剂的发展。