Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated
Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated
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DOI：
10.1021/tx034195a
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发表时间：
2004-01-01
影响因子：
4.1
通讯作者：
Uetrecht, JP
中科院分区：
文献类型：
--
作者：
Masson, MJ;Uetrecht, JP
大多数服用与特殊药物反应相关的药物的患者对药物耐受，不会出现不良反应。了解药物耐受的机制很重要，因为它可以提供洞察为什么一些患者会出现特殊反应，而另一些患者不会。采用D-青霉胺诱导自身免疫的Brown挪威大鼠模型作为特异性药物诱导自身免疫模型。低剂量(5 mg/d)D-青霉胺预处理两周后，完全阻止了60-80%的大鼠在高剂量(20 mg/d)D-青霉胺治疗后出现的所有自身免疫的临床症状。低剂量预处理也可抑制大剂量D-青霉胺所致的IgE和IL-4mRNA表达的升高。进行了实验以确定低剂量耐受性是代谢的还是免疫学的。研究发现，低剂量耐受具有免疫介导耐受的关键特征：记忆、过继转移耐受的脾细胞以及调节性细胞因子的产生。为了提供对阻止或逆转已建立的耐受性的因素的理解，我们调查了诱导和维持耐受性的条件。在低剂量暴露期间，通过操纵免疫系统来研究耐受性的诱导。在低剂量暴露期间，用氯屈膦酸盐填充的脂质体耗尽抗原提呈细胞的巨噬细胞亚群，或用他克莫司抑制T细胞，可部分防止耐受性的诱导。此外，在用PolyI：C低剂量预处理期间，通过反复刺激免疫系统，完全阻止了耐受的诱导。为了研究耐受的持久性，在耐受诱导后刺激免疫系统，试图打破耐受。脂多糖和PolyI：C均以剂量依赖的方式逆转耐受。这些结果表明，短期小剂量预处理可诱导对D-青霉胺自身免疫的免疫耐受。
Most patients taking drugs associated with idiosyncratic drug reactions tolerate the drug and do not develop adverse reactions. Understanding the mechanism of tolerance to drugs is important as it could provide insight into why some patients develop idiosyncratic reactions and others do not. The Brown Norway rat model of D-penicillamine-induced autoimmunity was used as a model of idiosyncratic drug-induced autoimmunity. Two weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally seen in 60-80% of rats treated with high dose (20 mg/day) D-penicillamine. Low dose pretreatment also prevented the increase in IgE and IL-4 mRNA characteristic of the response to high dose D-penicillamine. Experiments were conducted to determine whether low dose tolerance is metabolic or immunological. It was found that low dose tolerance possesses key characteristics of immune-mediated tolerance: memory, splenocytes that adoptively transfer tolerance, and regulatory cytokine production. To provide an understanding of the factors that can prevent or reverse established tolerance, the conditions for inducing and maintaining tolerance were investigated. Tolerance induction was investigated by manipulating the immune system during the period of low dose exposure. The induction of tolerance was partially prevented by depleting the macrophage subset of antigen presenting cells with clodronate-filled liposomes or by inhibiting T cells with tacrolimus during the period of low dose exposure. As well, the induction of tolerance was completely prevented by repeatedly stimulating the immune system throughout the period of low dose pretreatment with poly I:C. To investigate the permanence of tolerance, the immune system was stimulated after tolerance induction in an attempt to break tolerance. Both LPS and poly I:C reversed tolerance in a dose-dependent manner. These results demonstrate that immune tolerance to D-penicillamine autoimmunity can be induced by short-term low dose pretreatment.