Burns R P, Ferbel B, Tomai M, Miller R, Gaspari A A
Department of Dermatology, 3M Pharmaceuticals, St. Paul, Minnesota, USA.
Clin Immunol. 2000 Jan;94(1):13-23. doi: 10.1006/clim.1999.4804.
Imiquimod (R-837) and its more potent derivative (R-848) are imidazoquinolines that have adjuvant activity in cultured human mononuclear cells. Its mechanism of action on epidermal antigen-presenting cells is not known. The purpose of the present investigation was to determine whether imiquimod and R-848 affect human epidermal Langerhans' cells' (LC) in vitro maturation. Pulse incubations (6-16 h) of cultured unfractionated epidermal cells or highly enriched LC suspensions with either imiquimod or R-848 (0. 05-5.0 microg/ml of culture medium) reproducibly enhanced their ability to induce T-cell proliferation in a primary mixed lymphocyte reaction. There was a 30 to 300% increase in T-lymphocyte proliferation induced by either imiquimod- or R-848-treated LC when compared to control, untreated LC. IFN-gamma secretion by T-lymphocytes stimulated by imiquimod- or R-848-treated LC was increased compared to control, untreated LC. After a 6-h incubation, phenotypic analysis of control-, imiquimod-, or R-848-treated LC indicated that such antigen-presenting cells were in an "intermediate" state of maturation (CD1a(+), HLA-DR, DP, DQ(bright+), CD40(low+), CD86(high+), and CD80(low+)). RNase protection assays demonstrated that either imiquimod or R-848 treatments increased steady-state transcripts encoding for IL-12 p40, IL-1beta, TNF-alpha, and IL-1 receptor antagonist by LC. These data indicate that imiquimod and R-848 dissociate the functional maturation (cytokine-mediated) and phenotypic maturation of epidermal LC. These data warrant further exploration for the use of imidazoquinoline-treated LC or other DC subsets for processing and presentation of viral peptides to Th-lymphocytes as a novel vaccine strategy to induce protective antiviral responses.
咪喹莫特（R - 837）及其更强效的衍生物（R - 848）是咪唑喹啉类化合物，在培养的人单核细胞中具有佐剂活性。其对表皮抗原呈递细胞的作用机制尚不清楚。本研究的目的是确定咪喹莫特和R - 848是否会影响人表皮朗格汉斯细胞（LC）的体外成熟。用咪喹莫特或R - 848（0.05 - 5.0微克/毫升培养基）对未分级的培养表皮细胞或高度富集的LC悬液进行脉冲孵育（6 - 16小时），可重复性地增强它们在初次混合淋巴细胞反应中诱导T细胞增殖的能力。与对照的未处理LC相比，经咪喹莫特或R - 848处理的LC诱导的T淋巴细胞增殖增加了30%至300%。与对照的未处理LC相比，经咪喹莫特或R - 848处理的LC刺激的T淋巴细胞分泌的IFN - γ增加。孵育6小时后，对对照、咪喹莫特或R - 848处理的LC进行表型分析表明，此类抗原呈递细胞处于成熟的“中间”状态（CD1a(+)、HLA - DR、DP、DQ(明亮+)、CD40(低+)、CD86(高+)和CD80(低+)）。核糖核酸酶保护分析表明，咪喹莫特或R - 848处理均可增加LC中编码IL - 12 p40、IL - 1β、TNF - α和IL - 1受体拮抗剂的稳态转录本。这些数据表明，咪喹莫特和R - 848使表皮LC的功能成熟（细胞因子介导）和表型成熟脱钩。这些数据值得进一步探索将咪唑喹啉处理的LC或其他树突状细胞亚群用于处理和呈递病毒肽给Th淋巴细胞，作为诱导保护性抗病毒反应的新型疫苗策略。
