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Functions and roles of pathogenic T cells in drug hypersensitivity

致病性T细胞在药物超敏反应中的功能和作用

基本信息

批准号：
15591173
负责人：
HASHIZUME Hideo
金额：
$ 2.18万
依托单位：
Hamamatsu University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

We investigated immunologically on the circulating lymphocytes from patients with drug-induced eruption including drug-induced hypersensitivity (DIHS) and acute generalized exanthematous pustulosis (AGEP). We experienced three cases of drug-induced hypersensitivity syndrome (DINS) associated with herpesvirus reactivation and investigation of the immunological characteristics of the circulating and skin-infiltrating lymphocytes. In tribenoside-induced DIHS, activated CD8+ T cells outnumbered CD4+ cells in both the circulation and the skin lesions. Upon in vitro stimulation with the drug, CD4+ cells proliferated and produced interferon-γ. The circulating CD8+ cells used limited T-cell receptor Vβs, some of which are restricted to cytomegalovirus-derived peptide in the context of the HLA-A2 haplotype. CD8+ cells and cytomegalovirus-containing cells closely co-localized in the skin lesions. These results suggested that CD4+ cells were drub reactive, whereas cytomegalovirus activated CD8+ c … More ells in the present case. In the other two cases of DIHS, phenotypes of the circulating lymphocytes similarly changed ; CD4+ cells activated first and CD8+ cells activated later during the course with hervesvirus reactivation at the same time. Therefore, these two cell types seemed to play a distinct role in DIMS.In three cases of AGEP, we established drug-reactive T cell clones/lines and investigated their function. These clones/lines proliferated in response to the causative drugs (stimulation index>1.5) and expressed CD3 and CD4/CD8 molecules. T-cell receptor Vβs that they used were heterogeneous. All the clones/lines were positive for CXCR-3 which is chemokine receptor for IP-10 produced by keratinocyles. Most of CD4+ clones/lines produced IL-2 and IFNN-γ, indicating to be Th1 cells. Interestingly, they produced large amount of TNF-α and IL-8, which attracts neutrophils. The functions of the pathogenic T cells reflect the clinical presentations manifesting neutrophilic abscesses in AGED. Less

本文对药物性药疹包括药物性超敏反应（DIHS）和急性泛发性暴露性脓疱病（AGEP）患者的外周血淋巴细胞进行了免疫学研究。我们经历了三例药物引起的过敏综合征（DINS）与疱疹病毒的再激活和调查的免疫学特征的循环和皮肤浸润淋巴细胞。在三苯皂甙诱导的DIHS中，在循环和皮肤病变中活化的CD 8 + T细胞的数量超过了CD 4+细胞。在体外用药物刺激后，CD 4+细胞增殖并产生干扰素-γ。循环中的CD 8+细胞使用有限的T细胞受体Vβ，其中一些仅限于HLA-A2单倍型背景下的巨细胞病毒衍生肽。CD 8+细胞和含巨细胞病毒的细胞在皮损中密切共定位。结果提示，CD 4+细胞是药物反应性的，而巨细胞病毒则激活CD 8+细胞。 ...更多信息在本案中。在另外两例DIHS中，循环淋巴细胞的表型也发生了类似的变化，在疱疹病毒再激活的同时，CD 4+细胞先激活，CD 8+细胞后激活。因此，这两种细胞类型似乎在DIMS中起着不同的作用。在三例AGEP中，我们建立了药物反应性T细胞克隆/系，并研究了它们的功能。这些克隆/系响应于致病药物而增殖（刺激指数>1.5）并表达CD 3和CD 4/CD 8分子。他们使用的T细胞受体Vβ是异质性的。所有的克隆/系对CXCR-3是阳性的，CXCR-3是由角质形成细胞产生的IP-10的趋化因子受体。大多数CD 4+细胞克隆/系产生IL-2和IFNN-γ，表明为Th 1细胞。有趣的是，它们产生大量的TNF-α和IL-8，吸引中性粒细胞。病原性T细胞的功能反映了老年性痴呆患者嗜酸性粒细胞增多的临床表现。少