Popovic Marija, Caswell Jeff L, Mannargudi Baskar, Shenton Jacintha M, Uetrecht Jack P
Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Chem Res Toxicol. 2006 Sep;19(9):1205-14. doi: 10.1021/tx0601152.
Nevirapine, used for the treatment of HIV infection, is associated with development of skin rash and liver toxicity. The mechanism of these idiosyncratic reactions is unknown. We have previously reported the discovery of a new animal model of nevirapine-induced skin rash in rats. When treated with nevirapine, Brown Norway rats developed red ears on about day 7 and skin rash on about day 21. On rechallenge, ears turn red within 24 h, and skin lesions develop by day 9. In the current study, we analyzed the time course of the sequence of events involved in the development of skin rash. Rats were treated with nevirapine for 7, 14, or 21 days or rechallenged with it for 0, 1, or 9 days. This treatment led to an increase in the total number of auricular lymph node T, B, and macrophage cells. There was also an increase in the activation/infiltration marker ICAM-1 and activation/antigen presentation marker MHC II in these cells compared with those from control rats. Immunohistochemistry analysis showed macrophage infiltration and ICAM-1 expression in the ears of treated rats as early as day 7 of treatment. Macrophage infiltration preceded T cell infiltration, which was not apparent until the onset of rash. Both MHC I and MHC II expression increased in the skin of nevirapine-treated rats that developed rash. A major inducer of MHC is IFNgamma. Although rechallenge with nevirapine led to a large increase in serum levels of IFNgamma, this was not observed during the treatment of naïve rats with nevirapine. These observations provide further clues to the mechanism of nevirapine-induced skin rash.
用于治疗HIV感染的奈韦拉平与皮疹和肝毒性的发生有关。这些特异反应的机制尚不清楚。我们之前报道了在大鼠中发现的一种新的奈韦拉平诱导皮疹的动物模型。用奈韦拉平治疗时，棕色挪威大鼠在约第7天耳朵变红，在约第21天出现皮疹。再次给药时，耳朵在24小时内变红，皮肤损伤在第9天出现。在当前研究中，我们分析了皮疹发生过程中一系列事件的时间进程。大鼠用奈韦拉平治疗7天、14天或21天，或再次给药0天、1天或9天。这种治疗导致耳淋巴结T细胞、B细胞和巨噬细胞总数增加。与对照大鼠相比，这些细胞中的活化/浸润标志物ICAM-1和活化/抗原呈递标志物MHC II也增加。免疫组织化学分析显示，早在治疗第7天，治疗大鼠的耳朵中就有巨噬细胞浸润和ICAM-1表达。巨噬细胞浸润先于T细胞浸润，T细胞浸润直到皮疹出现才明显。在出现皮疹的奈韦拉平治疗大鼠的皮肤中，MHC I和MHC II表达均增加。MHC的主要诱导剂是IFNγ。虽然用奈韦拉平再次给药导致血清IFNγ水平大幅升高，但在用奈韦拉平治疗初治大鼠期间未观察到这种情况。这些观察结果为奈韦拉平诱导皮疹的机制提供了进一步线索。
