ENDOCRINE-IMMUNE INTERACTIONS

内分泌免疫相互作用

• 批准号: 3778554
• 负责人: G P CHROUSOS
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3778554
• 关键词: Cushing's syndrome; arthritis; autoimmune disorder; corticotropin releasing factor; drug screening /evaluation; endocrine disorder chemotherapy; endocrine pharmacology; gender difference; glucocorticoids; hormone inhibitor; hormone regulation /control mechanism; human subject; human therapy evaluation; human tissue; hypothalamic pituitary axis; immunomodulators; inflammation; laboratory rat; mifepristone; pituitary adrenal axis; progestins

Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. We have tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis, when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. RU 486 potentiated the inflammatory/immune response to a standard stimulus in intact animals, suggesting that glucocorticoids exert anti-inflammatory/immunosuppressive effects at physiological levels. We recently demonstrated that corticotropin releasing hormone (CRH) is produced locally at the site of inflammation and has profound pro- inflammatory effects at an autocrine/paracrine level. We have called this "immune" CRH. Glucocorticoids suppress, and RU 486 markedly augments local secretion of immune CRH at an inflammatory site. Immune CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, and menstruation. RU 486 allowed the identification of a central nervous system defect in rats prone to arthritis. In these animals the glucocorticoid response to stress-mediators is inadequate to restrain the immune system following an insult. The actual defect is global and located at the level of the hypothalamic CRH neuron, which responds poorly to all its known stimulants, including several cytokines, as well as serotonin, acetylcholine and norepinephrine. This pathophysiologic mechanism is novel and its relevance to human arthritis and autoimmune disease will be examined.

存在临床上有用的雌激素、雄激素和雌激素受体拮抗剂。 盐皮质激素 糖皮质激素或孕激素的拮抗剂 具有潜在的临床应用价值。 的 该项目的目标是开发和研究分子机制 的行动和人类应用的拮抗剂，这两个 类固醇的种类 我们已经测试了一种糖皮质激素的原型 拮抗剂（RU 486）。 该化合物 对人糖皮质激素和孕酮受体有很强的亲和力 并且在小实验动物中没有激动剂作用。 给予 RU 486引起非人灵长类动物或人的血浆浓度长期升高， 促肾上腺皮质激素、皮质醇和精氨酸加压素，所有这些变化都可以通过 既往使用糖皮质激素（地塞米松）。 这 表明抗糖皮质激素可用于挑战 下丘脑-垂体-肾上腺轴，当需要临床试验时， 有此轴疾病的患者。 抗糖皮质激素治疗 由于异位ACTH分泌导致的重度库欣综合征患者，或 肾上腺皮质肿瘤引起缓解的临床表现， 皮质醇过多症 RU 486增强了炎症/免疫反应， 在完整动物中的标准刺激，表明糖皮质激素 在生理水平发挥抗炎/免疫抑制作用。 我们最近证明促肾上腺皮质激素释放激素（CRH）是 在炎症部位局部产生，并具有深刻的亲， 自分泌/旁分泌水平的炎症作用。 我们称之为 免疫CRH 糖皮质激素抑制，RU 486显著增强 在炎症部位局部分泌免疫CRH。 免疫CRH是 在卵巢和子宫内膜中发现，它可能参与 排卵、黄体溶解和月经的炎症现象。 RU 486 允许识别大鼠的中枢神经系统缺陷 容易患关节炎 在这些动物中， 应激介质不足以抑制免疫系统， 侮辱。 实际缺陷是全局的，位于 下丘脑CRH神经元，它对所有已知的CRH神经元的反应都很差， 兴奋剂，包括几种细胞因子，以及血清素， 乙酰胆碱和去甲肾上腺素。 这种病理生理机制是 新的，它与人类关节炎和自身免疫性疾病的相关性将是 考察