Kalthoff F S, Chung J, Musser P, Stuetz A
Novartis Research Institute, A-1235 Vienna, Austria.
Clin Exp Immunol. 2003 Sep;133(3):350-9. doi: 10.1046/j.1365-2249.2003.02225.x.
Clinically, corticosteroids (CS) are among the first line drugs in the therapy of autoimmune and allergic diseases and potently inhibit the activation of immune cells. However, due to their pleiotropic mode of action, the prolonged use of CS is generally associated with a range of undesirable side-effects. In this study, we compared the activity of pimecrolimus, a novel immunomodulatory drug for the treatment of inflammatory skin disorders, and the CS dexamethasone (Dex) and beta-methasone-valerate (beta-MSV) in different in vitro assays addressing the cytokine-induced differentiation and maturation of monocyte-derived dendritic cells (M-DC), the susceptibility of M-DC to drug-induced apoptosis and the potency of differentiated M-DC to induce primary T cell activation. In contrast to pimecrolimus, Dex and beta-MSV strongly induced apoptosis of M-DC precursors if added at the start of the DC differentiation culture. Flow cytometric analysis of surviving cells on day 6 of culture showed that the expression of several DC-specific antigens such as CD1a, CD40 and CD80 was inhibited by 50% to 80% at concentrations between 1 nm and 10 nm of either Dex or beta-MSV. Furthermore, the presence of CS during the final maturation of M-DC inhibited the synthesis of IL-12p70, the expression of critical DC costimulatory molecules, such as CD83 and CD86 and impaired their ability to activate primary CD4+ T cell proliferation. In contrast, pimecrolimus did not inhibit the LPS-induced secretion of IL-12, surface expression of costimulatory molecules or the maturation of M-DC into potent stimulators of T cells. Taken together, these data indicate that pimecrolimus does not interfere with the differentiation and viability of dendritic cells and their precursors or with the function of mature M-DC to prime naïve T lymphocytes, and thus may have a lower potential than CS to interfere with DC-mediated immunosurveillance.
临床上，皮质类固醇（CS）是自身免疫性疾病和过敏性疾病治疗的一线药物之一，能有效抑制免疫细胞的激活。然而，由于其多效性作用方式，长期使用CS通常会伴随一系列不良副作用。在本研究中，我们比较了一种用于治疗炎症性皮肤病的新型免疫调节药物吡美莫司与CS地塞米松（Dex）和倍他米松戊酸酯（β-MSV）在不同体外试验中的活性，这些试验涉及细胞因子诱导的单核细胞衍生树突状细胞（M-DC）的分化和成熟、M-DC对药物诱导凋亡的敏感性以及分化的M-DC诱导原代T细胞激活的能力。与吡美莫司相反，如果在DC分化培养开始时添加Dex和β-MSV，它们会强烈诱导M-DC前体细胞凋亡。培养第6天对存活细胞的流式细胞术分析表明，在1 nM至10 nM的Dex或β-MSV浓度下，几种DC特异性抗原如CD1a、CD40和CD80的表达被抑制了50%至80%。此外，在M-DC最终成熟过程中CS的存在抑制了IL-12p70的合成、关键DC共刺激分子如CD83和CD86的表达，并损害了它们激活原代CD4+T细胞增殖的能力。相比之下，吡美莫司不抑制LPS诱导的IL-12分泌、共刺激分子的表面表达或M-DC向T细胞有效刺激剂的成熟。综上所述，这些数据表明吡美莫司不会干扰树突状细胞及其前体的分化和活力，也不会干扰成熟M-DC启动幼稚T淋巴细胞的功能，因此与CS相比，其干扰DC介导的免疫监视的可能性可能更低。
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