Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation.
Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation.
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DOI：
10.1084/jem.20100124
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发表时间：
2010-10-25
期刊：
影响因子：
--
通讯作者：
Ahmed R
中科院分区：
文献类型：
--
作者：
Araki K;Gangappa S;Dillehay DL;Rouse BT;Larsen CP;Ahmed R
病原性病毒特异性T细胞即使在免疫抑制条件下也可以引起细胞因子风暴和致命疾病。最近，几例致命的淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染发生在接受免疫抑制性钙调磷酸酶抑制剂FK 506治疗的移植受者中。这些发现是令人惊讶的，因为LCMV是一种非细胞溶解病毒。为了解非溶细胞病毒如何在免疫抑制条件下引起疾病，我们使用小鼠LCMV模型，发现与人移植受体中的观察结果相似，FK 506处理小鼠的LCMV感染导致致死性疾病，其特征为病毒血症、缺乏血清转化和组织中极轻微的淋巴细胞浸润。然而，尽管明显缺乏抗病毒免疫应答，但这种疾病是由病毒特异性T细胞精心策划的。FK 506不能阻止LCMV特异性T细胞的产生和增殖，而是改变了它们的分化，使这些效应T细胞失去了控制病毒的能力，但仍然能够介导疾病。这些致病性T细胞引发了以高水平的肿瘤坏死因子（TNF）和白细胞介素6（IL-6）为特征的细胞因子风暴，并且T细胞的耗尽或这些炎性细胞因子的阻断防止了致命疾病。我们的研究表明，抑制钙调磷酸酶可以产生致病性T细胞，并表明T细胞介导的病毒性疾病，甚至可以在免疫抑制的条件下发生。此外，我们确定了一种潜在的策略（阻断TNF和IL-6），用于治疗有病毒感染急性并发症的移植受者。
Pathogenic virus-specific T cells can inflict a cytokine storm and lethal disease even in immunosuppressive conditions. Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse LCMV model and found that, similar to the observations in human transplant recipients, LCMV infection of FK506-treated mice resulted in a lethal disease characterized by viremia, lack of seroconversion, and minimal lymphocytic infiltrates in the tissues. However, despite the apparent absence of an antiviral immune response, this disease was orchestrated by virus-specific T cells. FK506 did not prevent the generation and proliferation of LCMV-specific T cells but instead altered their differentiation so that these effector T cells lost the ability to control virus but were still capable of mediating disease. These pathogenic T cells initiated a cytokine storm characterized by high levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6), and depletion of T cells or blockade of these inflammatory cytokines prevented the lethal disease. Our study shows that inhibiting calcineurin can generate pathogenic T cells and indicates that T cell–mediated viral disease can occur even under conditions of immunosuppression. Furthermore, we identify a potential strategy (blockade of TNF and IL-6) for treatment of transplant recipients who have acute complications of viral infection.
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影响因子：
4.4
作者：
Grayson, JM;Harrington, LE;Ahmed, R
通讯作者：
Ahmed, R
DOI：
10.1084/jem.20061496
发表时间：
2006-10-02
期刊：
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影响因子：
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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