INTERLEUKIN-2 PRODUCTION IN SJOGREN'S SYNDROME

干燥综合征中白细胞介素 2 的产生

• 批准号: 3223104
• 负责人: NORMAN TALAL
• 金额: $ 15.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3223104
• 关键词: B lymphocyte; Sjogren's syndrome; autoantibody; autoimmune disorder; calcium flux; enzyme linked immunosorbent assay; exocrine glands; human subject; interleukin 2; ion exchange chromatography; ionomycin; lymphoma; messenger RNA; northern blottings; phosphatidylinositols; polyamines; rheumatoid arthritis

Primary Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by 1) serum autoantibodies, 2) increased numbers of CD5+ B cells, 3) lymphocytic infiltration of salivary, lacrimal and other exocrine glands with a tendency to generalized lymphoproliferation that can terminate as a malignant lymphoma. The long-term objective of this application is to acquire knowledge leading to 1) a better understanding of the mechanisms responsible for the immune dysregulation in SS, and 2) possible development of new therapeutic modalities (such as polyamine inhibitors) for this disease. Peripheral blood mononuclear cells (PBMNC) from SS patients produce decreased amounts of interleukin-2 (IL-2) following stimulation with PHA or anti-CD3. There is also a transmembrane signalling defect in SS T cells revealed by exposure to PMA and ionomycin. Since oxidation products of polyamines diminish IL-2 production by normal and rheumatoid arthritis (RA) T cells, a similar mechanism may be operating and primary SS. The specific aims and methodologies are the following: 1. Measure polyamine levels (by HPLC), IL2 production (by bioassay) and the effect of polyamine inhibitors (like DEMO) on IL2 production in SS PBMNC. 2. Measure IL2 mRNA levels in SS PBMNC (by slot and Northern blots) and identify possible pre- or post-transcriptional defects (hydrolysis of phosphoinositides by ion exchange chromatography, rise in intracellular calcium by Indo-1 and FACS analysis, diacylglycerol-dependent activation, IL2 protein biosynthesis and secretion by ELISA). 3. Attempt to correct a possible defect in SS by polyamine inhibitors, or create a defect in normal PBMNC using polyamines plus polyamine oxidase.

原发性干燥综合征是一种慢性自身免疫性疾病 特征为1）血清自身抗体，2）CD 5 + B数量增加 细胞，3）唾液、泪腺和其他外分泌的淋巴细胞浸润 具有全身淋巴增生倾向的腺体， 最后是恶性淋巴瘤 长期目标是 应用是为了获得知识，导致1）更好地理解 SS中免疫失调的机制，以及2） 可能开发新的治疗方式（如多胺 抑制剂）治疗这种疾病。 外周血单个核细胞（PBMNC） SS患者产生的白细胞介素-2（IL-2）减少 用PHA或抗CD 3刺激后。 也有一个跨膜 通过暴露于PMA和离子霉素揭示SS T细胞中的信号传导缺陷。 由于多胺的氧化产物减少了正常人IL-2的产生， 和类风湿性关节炎（RA）T细胞，一个类似的机制可能是运作 主要SS 具体目标和方法如下： 1. 测量多胺水平（通过HPLC）、IL 2产生（通过生物测定）和 多胺抑制剂（如DEMO）对SS中IL 2产生的影响 PBMNC。 2. 测量SS PBMNC中的IL 2 mRNA水平（通过狭缝和北方印迹）， 鉴定可能的转录前或转录后缺陷（ 离子交换色谱法测定磷酸肌醇， 通过Indo-1和FACS分析的钙，二酰基甘油依赖性活化， 通过ELISA测定IL 2蛋白的生物合成和分泌）。 3. 尝试通过多胺抑制剂纠正SS中可能存在的缺陷，或 使用多胺加多胺氧化酶在正常PBMNC中产生缺陷。