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AUTACOIDS AS PHARMACOLOGIC MODIFIERS OF IMMUNITY

Autacoids 作为免疫药理学调节剂

基本信息

批准号：
3135591
负责人：
KENNETH L MELMON
金额：
$ 25.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-06-01 至 1993-05-31
项目状态：
已结题

项目摘要

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确定生物学的重要性，选择的自体免疫调节剂的治疗潜力。的证明这一建议的关键数据包括以下事实：1）已经发现炎症调节小鼠和人模型免疫和2）已发现组胺同系物和共轭物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H1或混合加H2效应的化合物，在体外构建和测试，并在体内进行初步测试。在过去的几年里，我们相信我们和其他人已经发展出了正当的理由，专注于组胺衍生物作为免疫调节剂。的理由包括发现组胺受体是非随机分布在鼠和人淋巴细胞上，参与免疫反应;组胺受体的表达是调节小鼠和人淋巴细胞的不同亚群，各种基于免疫学的刺激（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过程中释放组胺;各种与免疫有关的刺激物释放组胺;在自体免疫物质中组胺单独释放HSF，以及一些化学引诱剂和迁移抑制剂因素;组胺在某些人体细胞中的作用可能与区室化腺苷酸环化酶或CAMP;组胺能够调节T细胞表面抗原。简而言之，组胺似乎受到胺局部机制的精确控制释放以及影响受体分布的局部因素和表达。建议研究1。主要是扩展了正在进行的研究，组胺抗组胺药对小鼠和人免疫模型的影响回应; 2.试图建立这样的分子机制， H1、H2或H1加H2刺激在高度确定的亚组中的作用细胞和免疫环境; 3.试图确定在受体和组织特异性同源物的体内设置机制组胺和抗组胺药的结合物可以修饰T细胞模型，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当性和可行性测试它们作为人体免疫调节剂的价值。