IMMUNE ALTERATIONS MEDIATED BY CONDITIONING

调理介导的免疫改变

• 批准号: 3386137
• 负责人: DONALD T LYSLE
• 金额: $ 17.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-15 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3386137
• 关键词: B lymphocyte; antibody; atenolol; beta adrenergic receptor; beta antiadrenergic agent; conditioning; electrostimulus; endogenous opioid; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; immune system; immunopharmacology; immunoregulation; inhibitor /antagonist; laboratory rat; lymph nodes; morphine; naltrexone; natural killer cells; neuroimmunomodulation; opioid receptor; physiologic stressor; psychological stressor; psychoneuroimmunology; spleen; stimulus /response; suppressor T lymphocyte

There is a growing body of evidence indicating the various forms of psychological stress as well as use of drugs such as the opioids can compromise immunologic function, and thus may act as cofactors in HIV progression. The objective of our research is to examine conditioned alterations in immune function induced by an aversive event (electric shock) or by opiate administration, and examine the receptor-mechanisms that play a role in those immunomodulatory effects. Our prior studies with rodents successfully demonstrated that a stimulus which has been paired with (or conditioned to) electric shock can itself induce pronounced and reproducible alterations in immune function. The first specific aim is to extend our investigations of immune alterations induced by a conditioned aversive stimulus. We plan to identify conditioned alterations in the number of T-helper and T-suppressor lymphocytes, B-lymphocytes, and natural killer cells in blood, spleen, and lymph nodes with flow cytometric analysis. We also propose to evaluate the effect of a conditioned stimulus on the in-vivo production of T-dependent and T-independent antibody. The second specific aim expands our investigation to include a different form of conditioning. Given the relationship between opioid drug use and HIV progression, and the fact that morphine represents a "positive" or appetitive rather than aversive stimulus, we will focus our investigations on conditioned morphine-induced alterations of immune function. Our preliminary work has indicated that stimuli paired with morphine administration can induce alterations of immune function, and the proposed plan is to conduct extensive assessments of these conditioned immune alterations. The third specific aim investigates the mechanism by which aversive and appetitive conditioned stimuli induce immune alterations by using standard pharmacological procedures for determining receptor mediation. The experiments proposed are based on ongoing investigations which indicate that both the opioid and beta-adrenergic systems are involved in conditioned immunomodulation. Those investigations have shown that administration of the opiate antagonist naltrexone prior to the presentation of the conditioned aversive stimulus dose-dependently blocked the reduction in the proliferative response of lymphocytes and the suppression of natural killer cell activity. Similarly, administration of the nonselective beta-adrenergic receptor antagonist propranolol blocked the reduction in the proliferative response of lymphocytes. We now propose to identify the subpopulation of receptors which play a role in these conditioned immunomodulatory effects by examining several more selective opioid and beta-adrenergic antagonists. In the opioid system, these include beta-funaltrexamine, an irreversible mu antagonist; nor- binaltorphimine, a kappa selective antagonist; naltrindole, a delta selective antagonist, and quaternary forms of naltrexone. In the beta- adrenergic system, these include the beta2 selective antagonist ICI-118- 551, and beta1 selective antagonists atenolol and metoprolol. The conduct of this research promises to enhance our knowledge of the complex interaction between the central nervous system and the immune system, and the escalating incidence of HIV infection makes urgent the need for this knowledge.

越来越多的证据表明 心理压力以及阿片类药物等药物的使用可以 免疫功能妥协，因此可以充当HIV中的辅助因子 进展。 我们研究的目的是检查条件 厌恶事件引起的免疫功能的改变（电气 冲击）或阿片类药物，并检查受体机制 这在那些免疫调节作用中起作用。 我们先前的研究 啮齿动物成功证明了已经配对的刺激 使用（或条件为）电击本身会引起明显的诱因，并且 免疫功能可再现的改变。 第一个具体目的是 扩展我们对条件诱导的免疫改变的研究 厌恶刺激。 我们计划确定条件变化 T-馆和T-抑制剂淋巴细胞，B淋巴细胞和天然 血液，脾和淋巴结中的杀伤细胞具有流式细胞术 分析。 我们还建议评估条件刺激的效果 关于T依赖性和T独立抗体的体体产生。 第二个特定目标扩大了我们的调查，包括不同的 调理形式。 鉴于阿片类药物使用之间的关系和 艾滋病毒的进展，吗啡代表“阳性”或 食欲而不是厌恶刺激，我们将集中精力调查 在有条件的吗啡诱导的免疫功能改变。 我们的 初步工作表明刺激与吗啡配对 给药可以诱导免疫功能的改变，并提出 计划将对这些条件免疫进行广泛评估 改变。 第三个特定目的调查了厌恶和厌恶的机制 使用标准刺激刺激刺激会诱导免疫改变 确定受体介导的药理程序。 这 提出的实验是基于正在进行的调查，表明 阿片类药物和β-肾上腺素能系统都参与 条件免疫调节。 这些调查表明 在之前给予阿片类拮抗剂纳曲酮 呈现条件厌恶刺激剂量依赖性阻塞 淋巴细胞增殖反应的减少和 抑制天然杀伤细胞活性。 同样，给予 非选择性β-肾上腺素能受体拮抗剂普萘洛尔阻塞 淋巴细胞增殖反应的减少。 我们现在建议 确定在这些受体中发挥作用的受体的亚群 通过检查更多选择性的条件免疫调节作用 阿片类药物和β-肾上腺素能拮抗剂。 在阿片类型系统中，这些 包括不可逆的MU拮抗剂Beta-Funaltrecamine；也不- Binaltorphimine，Kappa选择性拮抗剂； Naltrindole，三角洲 纳曲酮的选择性拮抗剂和第四纪形式。 在beta- 肾上腺素能系统，其中包括beta2选择性拮抗剂ICI-118- 551和beta1选择性拮抗剂atenolol和metoprolol。 行为 这项研究有望增强我们对复杂的知识 中枢神经系统与免疫系统之间的相互作用，以及 艾滋病毒感染的发病率不断增加，因此需要 知识。