CHLORPROMAZINE, IMMUNOGENETICS AND TARDIVE DYSKINESIA

氯丙嗪、免疫遗传学和迟发性运动障碍

• 批准号: 3377381
• 负责人: ROSA T CANOSO
• 金额: $ 6.7万
• 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/3377381
• 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)的慢性治疗与糖尿病的发生有关 抗核抗体、IgM-狼疮抗凝剂和多克隆上调 免疫球蛋白M。这些自身抗体(Aab)在遗传上更普遍。 人类白细胞抗原高频率提示的易感个体 AAB患者血清中的BW44抗原。初步研究表明， 人类白细胞抗原BW44携带者迟发性运动障碍的严重程度增加 和AAB。此外，在CPZ停止后，这些异常情况仍然存在 当治疗之后使用其他吩噻嗪类药物时。 在这项研究中，我们建议研究(1)体液、细胞和遗传学 与自身抗体产生有关的异常和(2) 这些发现与精神疾病暴露人群的临床相关性 去CPZ。为此，我们计划评估两组Well患者 精神分裂症和分裂情感障碍的明确诊断，一 使用CPZ治疗，另一组使用其他抗精神病药物 吩噻嗪类药物。最后一组将作为控制组。这两个小组将 对组织进行分型并研究是否存在抗核自身抗体 材料(ANA)、磷脂(狼疮抗凝剂)、神经元组织 (抗神经抗体)、抗T细胞抗体和淋巴细胞亚群。 他们的外周T细胞亚群将用单克隆法研究 针对外周T淋巴细胞表面抗原的抗体。调查结果 将与认知功能障碍的存在相关 以及由韦氏评分和AIMS评分确定的运动障碍， 分别进行了分析。 我们假设有一种遗传易感性导致了 CPZ诱导的自身抗体受人类白细胞抗原BW44的调节。这个记号笔 与产生针对调节性T细胞的自身抗体有关 淋巴细胞亚群继发免疫稳态改变，B细胞 高反应性和增强自身抗体的产生。这些 自身抗体可能与核物质、膜发生交叉反应 磷脂和神经元组织对迟滞严重程度的调节 运动障碍。