AUTACOIDS AS PHARMACOLOGIC MODIFIERS OF IMMUNITY

Autacoids 作为免疫药理学调节剂

• 批准号: 3135590
• 负责人: KENNETH L MELMON
• 金额: $ 28.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-06-01 至 1992-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3135590
• 关键词: antihistamines; cardiovascular transplantation; cell cell interaction; cell population study; cellular immunity; cytotoxic T lymphocyte; drug design /synthesis /production; drug metabolism; guinea pigs; helper T lymphocyte; histamine; histamine receptor; histocompatibility; human subject; immunomodulators; immunopharmacology; immunoregulation; immunosuppression; inflammation; laboratory mouse; laboratory rabbit; laboratory rat; lymphokines; mitogens; pharmacokinetics; receptor expression; suppressor T lymphocyte; tissue /cell culture

This work seeks to further define the biologic importance and therapeutic potential of selected autocoids as immune modulators. The key data justifying this proposal include the facts that 1) Mediators of inflammation have been found to modulate murine and human models of immunity and 2) Congeners and conjugates of histamine have been found that affect only lymphocytes no other tissues. In the case of histamine derivatives, compounds with either pure Hl or mixed plus H2 effects have been constructed and tested in vitro and preliminarily tested in vivo. In the last years, we believe we and others have developed justification for focusing on histamine derivatives as immune modulators. The justification includes findings that receptors histamine are non-randomly distributed on murine and human lymphocytes that participate in immune response; the expression of histamine receptors is modulated on distinct subsets of murine and human lymphocytes by a variety of immunologically based stimuli (e.g., mitogens, the mixture of cell types in an MLR, the various lymphokines in the environment, and the stage of the immune response); the amine is stored in the tissues very frequently associated with immune responses; some lymphokines released during an immune response release histamine; a variety of immune-related stimuli release histamine; of the autacoids histamine alone releases HSF, and some chemoattractants and migration inhibitory factors; histamine effects in some human cells may relate to compartmentalized adenylate cyclase or CAMP; and histamine is capable regulating T cell surface antigens. In short, cellular responses to histamine seem exquisitely controlled by localized mechanisms of amine release as well as local factors that impact on receptor distribution and expression. The proposed study 1. primarily extends ongoing studies on the effects of histamine antihistamine on models of murine and human immune responses; 2. attempts to establish so the molecular mechanisms of the effects of Hl, H2, or Hl plus H2 stimulation in highly defined subsets of cells and immune circumstances and; 3. attempts to determine the in vivo setting mechanisms by which receptor and tissue specific congeners and conjugates of histamine antihistamines can modify models of T cell dependent and independent immune responses. Ultimately, we hope to determine the appropriateness and feasibility to transfer the compounds for testing their value as immune modulators in man.

这项工作旨在进一步定义生物重要性和 选定的自体类固醇作为免疫调节剂的治疗潜力。这个 支持这一提议的关键数据包括以下事实：1)调解人 炎症已被发现调节小鼠和人类模型 免疫和组胺的同系物和结合物已被发现 这只影响淋巴细胞，不影响其他组织。在组胺的情况下 衍生物，具有纯hl或混合加h2效应的化合物 已在体外构建和测试，并在体内进行了初步测试。 在过去的几年里，我们相信我们和其他人已经找到了理由 专注于组胺衍生物作为免疫调节剂。这个 正当理由包括发现受体组胺是 在小鼠和人淋巴细胞上非随机分布 参与免疫反应；组胺受体的表达 对小鼠和人淋巴细胞不同亚群的调节作用 各种基于免疫的刺激(例如，有丝分裂原、 MLR中的细胞类型、环境中的各种淋巴因子以及 免疫反应的阶段)；胺储存在组织中 经常与免疫反应有关；一些淋巴因子 在免疫反应中释放的组胺；各种 与免疫相关的刺激释放组胺；类海龙中的组胺 单独释放HSF，以及一些化学诱导剂和迁移抑制 因素；某些人类细胞中的组胺效应可能与 区域化的腺苷环化酶或cAMP；组胺能够 调节T细胞表面抗原。简而言之，细胞对 组胺似乎由胺的局部机制巧妙地控制 释放以及影响受体分布的局部因素 和表情。 拟议的研究1.主要是扩展正在进行的关于影响的研究 组胺类抗组胺药对小鼠和人免疫模型的影响 反应；2.试图建立这样的分子机制 高清晰度子集中HL、H2或HL加H2刺激的效果 细胞和免疫环境；3.试图确定 受体和组织特异性同系物的体内设定机制 组胺和抗组胺药物的结合物可以改变T细胞的模型 依赖和独立的免疫反应。最终，我们希望 确定转移化合物的适宜性和可行性 用于测试它们在人体内作为免疫调节剂的价值。