CHLORPROMAZINE, IMMUNOGENETICS AND TARDIVE DYSKINESIA

氯丙嗪、免疫遗传学和迟发性运动障碍

• 批准号: 3377380
• 负责人: ROSA T CANOSO
• 金额: $ 6.71万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1986-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3377380
• 关键词: T lymphocyte; antigen antibody reaction; antinuclear autoantibody; autoantibody; chlorpromazine; cognition; drug adverse effect; gene expression; human population genetics; human subject; human therapy evaluation; immunogenetics; immunoglobulin M; neuromuscular disorder chemotherapy; schizophrenia; surface antigens; tardive dyskinesia

Chronic therapy with chlorpromazine (CPZ) is associated with development of antinuclear antibodies, an IgM-lupus anticoagulant and polyclonal elevation of IgM. These autoantibodies (AAB) are more prevalent in genetically susceptible individuals as suggested by the high frequency of the HLA antigen BW44 in patients with AAB. Preliminary studies indicate that the severity of tardive dyskinesia is increased among patients with HLA-BW44 and AAB. Also, these abnormalities persist after discontinuation of CPZ when therapy is followed by other phenothiazines. In this study we propose to investigate (1) humoral, cellular and genetic abnormalities associated with the production of autoantibodies and (2) the clinical relevance of these findings to the psychiatric population exposed to CPZ. To this effect we plan to evaluate 2 groups of patients with well defined diagnosis of schizophrenia and schizoaffective disorders, one treated with CPZ and the other with neuroleptic agents other than phenothiazines. The last group will serve as control. The two groups will be tissue typed and studied for the presence of autoantibodies to nuclear material (ANA), phospholipids (lupus anticogulant), neuronal tissue (antineuronal antibodies), anti T cell antibodies and lymphocyte subsets. Their peripheral T cell subset profile will be studied with monoclonal antibodies against peripheral T lymphocyte surface antigens. The findings will be correlated with the presence of impairment in cognitive functions and movement disorders as determined by the Wechsler Scale and AIMS score, respectively. We postulate that there is a genetic predisposition to the production of CPZ induced autoantibodies regulated by the HLA marker BW44. This marker is associated with the production of autoantibodies against a regulatory T lymphocyte subset with subsequent alteration of immune homeostasis, B cell hyper-reactivity and enhanced production of autoantibodies. These autoantibodies may cross-react with nuclear material, membrane phospholipids and neuronal tissue modulating the severity of tardive dyskinesia.

氯丙嗪（CPZ）的长期治疗与以下疾病的发生有关： 抗核抗体、IgM-狼疮抗凝剂和多克隆升高 的IgM。 这些自身抗体（AAB）在遗传学上更普遍。 易感个体，如HLA的高频率所示 AAB患者的BW 44抗原 初步研究表明， HLA-BW 44患者迟发性运动障碍的严重程度增加 和AAB。 而且，这些异常在CPZ停药后持续存在 当治疗后使用其他吩噻嗪类药物时。 在这项研究中，我们建议调查（1）体液，细胞和遗传 与自身抗体产生相关的异常和（2） 这些发现与精神病人群的临床相关性 在CPZ。 为此，我们计划评估2组患者， 精神分裂症和情感性精神障碍的明确诊断， 用CPZ治疗，另一个用除 吩噻嗪。 最后一组作为对照组。 两个小组将 进行组织分型，并研究是否存在抗核抗体 材料（ANA）、磷脂（狼疮抗凝剂）、神经元组织 （抗神经元抗体）、抗T细胞抗体和淋巴细胞亚群。 将使用单克隆抗体研究他们的外周T细胞亚群谱 抗外周T淋巴细胞表面抗原的抗体。 这些发现 将与认知功能受损相关 以及由韦氏量表和AIMS评分确定的运动障碍， 分别 我们假设，有一种遗传倾向的生产， CPZ诱导的自身抗体受HLA标记物BW 44调节。 该标记 与针对调节性T细胞的自身抗体的产生有关 淋巴细胞亚群伴免疫稳态改变，B细胞 高反应性和自身抗体的产生增强。 这些 自身抗体可与核物质、膜 磷脂和神经组织调节迟发性痴呆的严重程度 运动障碍