Cell-Mediated Antiretroviral Drug Transport in the Lymph Node

摘要 最近在人类和灵长类动物身上进行的体内研究表明，用于抑制 艾滋病毒并不均匀地分布在淋巴组织中，存在于血浆中的药物可能 完全不存在于同一病人的淋巴结中。这一发现的临床意义并不是很好。 明白，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 从血液和液体淋巴运输到淋巴结的是排斥机制，而 淋巴结的精确三维几何形状可以解释不同淋巴之间药物渗透的差异 甚至在同一淋巴结的不同位置之间。除了免费的毒品运输模式外， 细胞内药物浓度是观察到的药物分布不均的另一个关键因素 在。淋巴细胞可以充当药物携带者，在贩运过程中顺便将药物运送到LN。蜂窝 传输速率比免费毒品传输速率慢一个数量级，因此细胞介导的贩运 不是血液灌流良好组织中药物浓度的主要贡献者。然而，在LN中，淋巴细胞使用 主动运输机制，允许它们通过上述屏障，因此通过这条途径进行运输 可以显著改变药物浓度的整体动态。在目标一中，我们将开发和验证 利用三维重建的小鼠淋巴结建立可扩展的药物进入淋巴小叶的预测模型。 该模型将配备完整的血管和鼻窦几何结构，并可用于预测药物分布 在任何小叶中并确定传输速率。在目标2中，我们将研究淋巴细胞在整个药物中所起的作用 通过功能性抗体阻断阻止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模型以更好地理解药物的作用机制 将其排除在淋巴结外，并指导克服它们的治疗方法的发展。

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.