Phosphodiesterases as Therapeutic Targets: Translational

基础科学研究：他汀类药物作为多效性免疫调节剂，已被报道可改善多发性硬化症小鼠模型的临床结果。由于结节样肉芽肿的病理形成部分是由高度极化的辅助性T细胞(Th)-1对未知感染或环境抗原的免疫反应所致，我们评估了阿托伐他汀和美伐他汀对以下方面的影响：(1)来自正常志愿者(NV)的血单核细胞来源的人树突状细胞(DC)上共刺激分子和激活分子的表达；(2)人类幼稚Th1淋巴细胞的分化；以及(3)肺结节病患者肺泡巨噬细胞产生Th1细胞因子和趋化因子。用流式细胞仪检测他汀类药物对未成熟DC对E.ColiLPS0128：B12共刺激和激活分子表达的影响。在培养的第4天至第6天，DC与50微米阿托伐他汀或美伐他汀孵育，可降低1微克/毫升的内毒素诱导的CD86、CD83、CD80和人类白细胞抗原-DR的表达。在Th1条件下培养的人脐血纯化的初始T淋巴细胞中，1微米阿托伐他汀可降低CXCR3+CD4+T淋巴细胞的表达。在结节病患者的肺泡巨噬细胞(未服用免疫抑制药物)中，30微米阿托伐他汀显著抑制IP-10、Mig、MCP-1、MIP-1α和MIP-1β的产生。在10微米时，阿托伐他汀也抑制IP-10和MCP-1的产生。因此，他汀类药物通过减少树突状细胞上共刺激分子和激活分子的表达，以及通过抑制T细胞分化和肺泡巨噬细胞中趋化因子的产生，可能对结节病患者有有益的影响。

Basic science studies: Statins act as pleiotropic immune modulators and have been reported to improve clinical outcomes in murine models of multiple sclerosis. Since the pathological formation of sarcoid granulomas is driven in part by highly polarized T helper (Th)-1 immune responses to unidentified infectious or environmental antigens, we evaluated effects of atorvastatin and mevastatin on (1) the expression of co-stimulatory and activation molecules on blood monocyte-derived human dendritic cells (DC) obtained from normal volunteers (NV); (2) differentiation of human naive Th1 lymphocytes; and, (3) production of Th1 cytokines and chemokines in alveolar macrophages from patients with pulmonary sarcoidosis. Effects of statins on the expression, by immature DC, of co-stimulatory and activation molecules in response to E.coli LPS 0128:B12 were assessed by flow cytometry. Incubation of DC with 50 micro M atorvastatin or mevastatin, between days 4 and 6 of culture, reduced the LPS(1 micro g/mL)-induced expression of CD86, CD83, CD80, and HLA-DR. In naive T-lymphocytes, purified from human umbilical cord blood and cultured under Th1 conditions, 1 micro M atorvastatin reduced the expression of CXCR3+ CD4+ T-lymphocytes. In alveolar macrophages from sarcoid patients (not on immunosuppressive medications), 30 micro M atorvastatin significantly inhibited the production of IP-10, Mig, MCP-1, MIP-1alpha;, and MIP-1Beta. At 10 micro M, atorvastatin also inhibited the production of IP-10 and MCP-1. Thus, statins, by decreasing the expression of co-stimulatory and activation molecules on dendritic cells, and by suppressing T-cell differentiation and chemokine production in alveolar macrophages, might have beneficial effects in patients with sarcoidosis.