IMMUNOPHARMACOGENETICS OF SCHIZOPHRENIA

精神分裂症的免疫药物遗传学

• 批准号: 3386843
• 负责人: EDMOND J YUNIS
• 金额: $ 30.66万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3386843
• 关键词: Jewish; MHC class I antigen; MHC class II antigen; alleles; antipsychotic agents; clozapine; dopamine; drug adverse effect; fluphenazine; genetic markers; granulocytopenia; histocompatibility typing; human subject; human therapy evaluation; immunogenetics; immunopharmacology; interleukin 2; leukocyte activation /transformation; major histocompatibility complex; mental disorder chemotherapy; pharmacogenetics; polymerase chain reaction; restriction fragment length polymorphism; schizophrenia; transferrin receptor

It is our hypothesis that a genetic basis reflected by MHC markers underlies pharmacologic response (both antipsychotic in the case of classical neuroleptic drugs and hematologic in the case of Clozapine) in patients with schizophrenia. Our application proposes a two arm study of immunogenetic mechanisms and pharmacologic response in schizophrenia. Specifically, we will examine the association between MHC markers, in particular, HLA-A1 and neuroleptic treatment response in patients with schizophrenia, since a decrease frequency of the HLA-A1 antigen was found in schizophrenics who were refractory to neuroleptic treatment. In a previous study, we reported an increase in HLA-A1 and a decrease in HLA-A2 in patients responsive to neuroleptic treatment. In other experiments, we will determine the therapeutic and supratherapeutic neuroleptic doses using lymphocytes from HLA-A1 positive versus negative patients to test the preferential effect of neuroleptics using an "in vitro" T cell activation model. The second arm of the proposal is based on an association that was found between the HLA B38 DR4 DQw3 haplotype (DRB1*0402 and DQB1*0302 alleles) and vulnerability to develop Clozapine-induced agranulocytosis among treatment refractory Jewish patients. In addition, among non-Jewish agranulocytosis patients, an increase in HLA-DR2 , DQw1 antigens has been found. We will confirm that the MHC susceptibility haplotype (B38, DR4, DQw3) predisposes Jewish patients to develop agranulocytosis following Clozapine treatment. Also, we will determine the specific alleles by PCR-RFLP and PCR-SSO methods for DR4, Dqw3 and DR2, Dqw1 involved in Clozapine-induced agranulocytosis susceptibility in order to provide a more reliable screening test for neuroleptic resistant individuals undergoing Clozapine treatment in order to minimize the risk of such complication. It is likely that a common MHC class II allele is responsible for agranulocytosis susceptibility between these two groups. However, the possibility of a second gene, yet to be discovered, and in linkage disequilibrium with MHC alleles and responsible for agranulocytosis susceptibility can not be eliminated at this moment.

我们的假设是，MHC标记反映的遗传基础 药物反应的基础(两种抗精神病药物在 经典抗精神病药与血液学在氯氮平治疗中的应用 精神分裂症患者。我们的应用程序建议进行两个臂的研究 精神分裂症的免疫遗传机制和药物反应。 具体地说，我们将研究MHC标记之间的关联，在 人类白细胞抗原-A1与抗精神病药物治疗反应的相关性 精神分裂症，因为发现了人类白细胞抗原A1的频率降低 对抗精神病药物治疗无效的精神分裂症患者。在一个 在之前的研究中，我们报告了人类白细胞抗原A1的增加和人类白细胞抗原A2的减少 对抗精神病药治疗有反应的患者。在其他实验中，我们 将确定治疗性和超治疗性抗精神病药物的剂量 检测人类白细胞抗原A1阳性和阴性患者的淋巴细胞 使用“体外”T细胞激活的抗精神病药物的优先效应 模特。提案的第二个分支基于一个关联，该关联是 发现于人类白细胞抗原B38 DR4 DQw3单倍型(DRB1*0402和DQB1*0302)之间 等位基因)和发生氯氮平引起的粒细胞缺乏症的易感性 在治疗难治的犹太患者中。此外，在非犹太人中 粒细胞缺乏症患者，人类白细胞抗原-DR2、DQw1抗原已升高 找到了。我们将确认MHC易感性单倍型(B38，DR4， DQw3)使犹太患者在以下情况下易患粒细胞缺乏症 氯氮平治疗。此外，我们将通过以下方式确定特定的等位基因 DR4、Dqw3和DR2、Dqw1的聚合酶链式反应-限制性片段长度多态性和聚合酶链式反应-SSO方法 氯氮平诱导的粒细胞缺乏症的易感性 对接受抗精神病药物治疗的个体进行可靠的筛查试验 氯氮平治疗，以将此类并发症的风险降至最低。 很可能是一个常见的MHC II类等位基因负责 两组粒细胞缺乏症易感性比较。然而， 第二个基因的可能性，尚未发现，并处于连锁中 粒细胞缺乏症与MHC等位基因的不平衡 目前还不能消除易感性。