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The objective of this study was to identify the molecular processes responsible …

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- Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream

Actinic keratosis (AK) are common, cutaneous, precancerous neoplasms appearing as rough, dry, scaly lesions that occur primarily on the sun-exposed skin of middle-aged and elderly people [1-3]. Although the exact mechanism of pathogenesis of AK development is unknown, part of the pathogenesis may involve suppression of the immune response against dysplastic cells [4]. It is believed that prolonged ultraviolet exposure changes the immune surveillance mechanism of the skin, contributing to the tolerance of tumor cells [5]. If left untreated, AK can progress to squamous cell carcinoma, a locally aggressive and occasionally metastatic tumor type [6]. Standard treatment of AK includes various types of surgical and chemical treatments [7,8], which are often associated with scarring and infection, and may not address sub clinical lesions [8].

Toll-like receptors (TLR) are pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) and play key roles in the activation of innate and adaptive immune responses [9,10]. Currently, 10 human TLRs have been identified. The natural ligands for all but TLR10 have also been identified [9]. Toll-like receptors are primarily expressed on immune cells such as monocytes, dendritic cells (DCs), and lymphocytes [11], but some TLRs are also expressed on nonimmune cells, including endothelial cells, epithelial cells, and keratinocytes [12].

The role of TLRs in the pathogenesis and treatment of dermatological diseases is increasingly recognized [13]. Imiquimod, a member of a class of drugs termed immune response modifiers has been shown to be a selective TLR7 agonist [[14,15], and unpublished internal data]. Imiquimod is the first TLR-agonist pharmaceutical product approved for human use, and is indicated for the topical treatment of external genital and perianal warts caused by human papilloma virus [16]. Recently, the approved indications have been expanded to include treatment of AK [17] and superficial basal cell carcinoma [18-20].

The antiviral and anti-tumor activity of imiquimod is believed to be due to the activation of the innate immune response, specifically activation of antigen-presenting cells such as monocytes, macrophages and plasmacytoid and myeloid DCs to induce interferon alpha (IFNα) and other cytokines and chemokines [21,15]. Imiquimod also enhances co stimulatory molecule expression important for triggering an adaptive immune response [15]. Topical application of the drug has been shown to induce IFNα and interleukin 6 (IL6) in AK lesions and external genital warts [22,23]. Imiquimod and the chemically related immune response modifier resiquimod have also shown potent vaccine adjuvant effects in mice and man [23-27]. Even though the immune-modulatory activity of imiquimod is well established, the precise molecular changes responsible for the antilesional activity of topically applied imiquimod in AK is not fully understood.

The objective of this study was to explore the molecular processes responsible for the antilesional activity of imiquimod in subjects with actinic keratosis using global gene expression profiling.

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