Modulation of Cell-Mediated Immune Function by Opiates

阿片类药物对细胞介导的免疫功能的调节

• 批准号: 6727618
• 负责人: PHILLIP Keith PETERSON
• 金额: $ 43.38万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727618
• 关键词: HIV envelope protein gp120; HIV infections; HeLa cells; apoptosis; cannabinoids; cellular immunity; clinical research; enzyme linked immunosorbent assay; flow cytometry; gene expression; helper T lymphocyte; human fetus tissue; human immunodeficiency virus 1; immunocytochemistry; indinavir; laboratory mouse; microglia; morphine; neurons; neurotoxins; opiate alkaloid; opioid receptor; tissue /cell culture; western blottings; zidovudine

DESCRIPTION (provided by applicant): Following recognition that intravenous drug users are a high risk group for development of AIDS, it was postulated that heroin could act as a cofactor in the pathogenesis of HIV-1, including development of neuroAIDS, via opiate-mediated immunosuppression and potentiation of viral expression. Despite a large body of supportive evidence, the impact of opiate abuse on HIV-1 pathogenesis remains controversial. Pharmacological considerations have been proposed as one explanation for the conflicting epidemiological and experimental data. The principal hypothesis to be tested in this research proposal is that pharmacologic factors, such as, concentration- and time-dependent responses and interactions with other drugs (i.e., cannabinoids and antiretroviral agents), will markedly influence how morphine, a major metabolite of heroin, and other mu-opioid receptor (MOR) ligands affect two critically important aspects of HIV-1 pathogenesis: 1) viral expression in CD4 and microglial cells, and 2) gp120 protein-induced apoptosis of CD4 and neuronal cells. To test this hypothesis, experiments have been designed that address three specific aims: 1) to investigate the effects of MOR ligands and cannabinoids on HIV-1 expression in CD4 and microglial cell cultures, 2) to investigate whether morphine alters the activity of antiretroviral drugs in these same cell culture models, and 3) to investigate the effects of MOR ligands and cannabinoids on gp120(IIIB)-induced apoptosis of CD4 and neurons. Cannabinoids have been chosen for these studies because of the widespread abuse of the cannabinoid marijuana and a literature demonstrating that cannabinoids also alter the immune system and have interactive effects with opioids. The antiretroviral agents we have chosen for our studies, zidovudine (AZT) and indinavir, are commonly used to treat HIV-1-infected, opiate-dependent patients. The studies designed for this research project promise to provide new insights into the mechanisms whereby opiates and cannabinoids affect the immunopathogenesis and neuropathogenesis of HIV-1 with the long-term goal of developing new approaches to the treatment of the devastating infection caused by this virus.

描述（由申请人提供）：在认识到静脉注射吸毒者是艾滋病发展的高风险群体之后，假设海洛因可能通过阿片类药物介导的免疫抑制和病毒表达增强，在HIV-1的发病机制中起辅助因素的作用，包括神经艾滋病的发展。尽管有大量的支持性证据，阿片类药物滥用对HIV-1发病机制的影响仍然存在争议。药理学方面的考虑已被提出作为流行病学和实验数据相互矛盾的一种解释。本研究计划要测试的主要假设是药理学因素，如浓度和时间依赖性反应以及与其他药物（即大麻素和抗逆转录病毒药物）的相互作用，将显着影响吗啡（海洛因的主要代谢物）和其他mu-阿片受体（MOR）配体如何影响HIV-1发病机制的两个至关重要的方面：1)病毒在CD4和小胶质细胞中的表达，2)gp120蛋白诱导CD4和神经元细胞凋亡。为了验证这一假设，我们设计了三个特定的实验：1)研究MOR配体和大麻素对CD4细胞和小胶质细胞培养中HIV-1表达的影响，2)研究吗啡是否改变这些细胞培养模型中抗逆转录病毒药物的活性，3)研究MOR配体和大麻素对gp120（IIIB）诱导的CD4细胞和神经元凋亡的影响。这些研究之所以选择大麻素，是因为大麻素被广泛滥用，而且有文献表明大麻素也会改变免疫系统，并与阿片类药物产生相互作用。我们为研究选择的抗逆转录病毒药物齐多夫定（AZT）和茚地那韦通常用于治疗感染艾滋病毒-1的阿片类依赖患者。为本研究项目设计的研究有望为阿片类药物和大麻素影响HIV-1免疫发病机制和神经发病机制的机制提供新的见解，长期目标是开发新的方法来治疗由这种病毒引起的破坏性感染。