TRANSENDOTHELIAL MIGRATION OF ACTIVATED MONOCYTES IN HIV

HIV 中激活的单核细胞的跨内皮迁移

• 批准号: 2270877
• 负责人: HOLLY H BIRDSALL
• 金额: $ 17.34万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-15 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2270877
• 关键词: B lymphocyte; HIV infections; T lymphocyte; astrocytes; cell adhesion; cell migration; cytomegalovirus; flow cytometry; human immunodeficiency virus 1; human tissue; immunocytochemistry; interleukin 1; laboratory rat; leukocyte activation /transformation; leukocyte adhesion molecules; monoclonal antibody; monocyte; nervous system infection; tissue /cell culture; vascular endothelium

Perivascular collections of macrophages and endogenous microglial cells appear to be major reservoirs of HIV- l within the central nervous system (CNS) and a source of viral and host cell products which have been implicated in the pathophysiology of dementia and other neurologic manifestations of HIV-l infection. Mechanisms responsible for the accumulation of these mononuclear leukocytes (MNL) in the CNS and, specifically, the contribution of peripheral blood leukocytes to these interstitial infiltrates have not been determined, nor is it clear whether the virus is carried to the CNS within infected PBL. Preliminary studies demonstrate that HIV- l infection stimulates cell surface expression of molecules on MNL which mediate adhesive interactions with endothelium and neural cells. Moreover we have found that peripheral blood monocytes from HIV- l infected subjects are frequently activated. They display increased quantities of these same adhesins and are more likely to adhere to cultured neural cells in vitro. The experiments proposed in this application will evaluate the ability of MNL from HIV-I infected subjects to migrate across endothelial cell monolayers. Using in vitro methods which allow us to harvest, enumerate and compare the phenotypes of leukocytes which have the capacity to adhere to, and migrate across endothelium, we propose to investigate whether HIV- l infected cells are particularly abundant in this population and evaluate whether infection with putatively "neurotropic" strains of HIV- l enhances their ability to migrate across endothelium. Factors which may modulate endothelial transmigration of MNL will also be investigated, including the effects of astrocytes growing in contiguity with endothelial monolayers, infection of endothelial cells with cytomegalovirus and stimulation with cytokines, such as IL- l, that are likely to be released by activated MNL or endothelial cells. Adhesive interactions between MNL, which have demonstrated their ability to migrate through endothelial barriers, and neural cells will be investigated in an attempt to identify the molecular basis for these interactions. Monoclonal antibodies (mAbs) specific for beta integrins, selectins and other molecules known to mediate heterotypic adhesive cellular interactions will be used in an attempt to block the binding of MNL to neural cells. We also plan to raise antibodies to ligands that resist the ability of presently available mAbs to block adhesive interactions in order to fully characterize the array of molecules used by HIV-l infected and/or activated MNL to attach to neural cells. Upon completion, we postulate that the proposed investigations will provide a better understanding of the mechanisms in HIV- l infected individuals which regulate trafficking of MNL across blood vessels and cause them to be retained within the CNS.

巨噬细胞和内源性小胶质细胞的血管周围收集 似乎是中枢神经系统中HIV-L的主要水库 （CNS）和病毒和宿主细胞产品的来源 与痴呆和其他神经系统的病理生理有关 HIV-L感染的表现。负责 这些单核白细胞（MNL）在中枢神经系统中的积累 具体而言，外周血白细胞对这些的贡献 尚未确定间隙浸润，也不清楚是否清楚 该病毒被携带到感染PBL内的中枢神经系统中。初步研究 证明HIV-L感染刺激了细胞表面表达 MNL上介导与内皮和内皮相互作用的MNL分子 神经细胞。此外，我们发现外周血单核细胞来自 经常激活受HIV感染的受试者。他们显示的增加 这些相同粘附素的数量，更有可能遵守 体外培养的神经细胞。提出的实验 应用将评估来自HIV-I感染受试者的MNL的能力 跨内皮细胞单层迁移。使用体外方法 这使我们能够收获，枚举和比较 有能力遵守和迁移的白细胞 内皮，我们建议研究HIV-HIV感染细胞是否是 在这个人群中特别丰富，并评估感染是否 HIV-L的预定“神经性”菌株增强了其能力 跨内皮迁移。可能调节内皮的因素 也将研究MNL的转移，包括 与内皮单层连续生长的星形胶质细胞，感染 内皮细胞具有巨细胞病毒和细胞因子刺激， 例如IL-L，可能会通过激活的MNL或 内皮细胞。 MNL之间的粘合性相互作用 证明了他们通过内皮障碍迁移的能力，并且 将研究神经细胞以识别分子 这些相互作用的基础。特异性的单克隆抗体（mAb） β整合素，选择素和其他已知可以介导异型的分子 粘合性蜂窝相互作用将用于试图阻止 MNL与神经细胞的结合。我们还计划提出抗体 抵抗目前可用单元格阻塞的能力的配体 粘合剂相互作用以充分表征 HIV-L感染和/或激活的MNL用于神经的分子 细胞。完成后，我们假设拟议的调查将 更好地了解感染HIV的机制 调节MNL跨血管贩运的个体 导致将它们保留在中枢神经系统中。