Stanley M A
University of Cambridge, Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, UK.
Clin Exp Dermatol. 2002 Oct;27(7):571-7. doi: 10.1046/j.1365-2230.2002.01151.x.
A central development of the past decade has been in our understanding of the interactions between, and interdependence of, the innate and adaptive immune responses. Innate immunity recognizes 'danger' signals and activates adaptive immunity in a targeted, appropriate and effective response. Dendritic cells and macrophages have a central role in this process, and pharmacological agents that modulate the functions of these cells could have therapeutic value. The imidazoquinolone compounds, of which imiquimod, formulated as Aldara trade mark, is the best characterized to date, are such molecules. Imiquimod and its homologues act by activating macrophages and other cells via binding to cell surface receptors, such as Toll receptor 7, thereby inducing secretion of pro-inflammatory cytokines, predominantly interferon (IFN)-alpha, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12. This locally generated cytokine milieu biases towards a Th1 cell mediated immune response with the generation of cytotoxic effectors, and this has been exploited clinically in the treatment of viral infections (human papillomavirus, herpes simplex virus, molluscum contagiosum) and nonmelanoma skin cancer. Imiquimod has been shown to be significantly more effective than placebo in clearing genital warts, and mechanism of action studies indicate that this is related to the ability to generate proinflammatory cytokines and a Th1 response. Intra-epithelial neoplasms of cutaneous and mucosal surfaces are associated with human papillomavirus infection and there is some evidence that immune response modifiers may have therapeutic value for these lesions. Topical immunotherapy with immunomodulators shows potential for effective and patient-friendly treatment of cutaneous viral infections. These compounds also have adjuvant properties that could significantly enhance conventional vaccine strategies.
过去十年的一个核心进展是我们对固有免疫反应和适应性免疫反应之间的相互作用及相互依存关系的理解。固有免疫识别“危险”信号，并以有针对性、适当且有效的方式激活适应性免疫。树突状细胞和巨噬细胞在这一过程中发挥核心作用，调节这些细胞功能的药物制剂可能具有治疗价值。咪唑喹啉酮化合物就是这样的分子，其中以Aldara商标上市的咪喹莫特是迄今特征最明确的。咪喹莫特及其同系物通过与细胞表面受体（如Toll样受体7）结合来激活巨噬细胞和其他细胞，从而诱导促炎细胞因子的分泌，主要是干扰素（IFN）-α、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-12。这种局部产生的细胞因子环境倾向于Th1细胞介导的免疫反应并产生细胞毒性效应物，这一点已在病毒感染（人乳头瘤病毒、单纯疱疹病毒、传染性软疣）和非黑色素瘤皮肤癌的治疗中得到临床应用。已证明咪喹莫特在清除尖锐湿疣方面比安慰剂显著更有效，作用机制研究表明这与产生促炎细胞因子和Th1反应的能力有关。皮肤和黏膜表面的上皮内瘤与人类乳头瘤病毒感染相关，有证据表明免疫反应调节剂可能对这些病变具有治疗价值。用免疫调节剂进行局部免疫疗法显示出有效且对患者友好地治疗皮肤病毒感染的潜力。这些化合物还具有佐剂特性，可显著增强传统疫苗策略。
