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Imiquimod, a topical immune response modifier, induces migration of Langerhans cells.

Suzuki H, Wang B, Shivji GM, Toto P, Amerio P, Tomai MA, Miller RL, Sauder DN.

Division of Dermatology, Sunnybrook Health Science Center, University of Toronto, Ontario, Canada.

Langerhans cells are bone marrow derived dendritic cells that represent the major antigen-presenting cells in the skin. Langerhans cells take up and process antigen within the epidermis and present processed antigen to T lymphocyte in the regional lymph nodes and thus form an integral part of the cutaneous immune response. The cutaneous immune response can be modified by a number of pharmacologic agents, including corticosteroids, cyclosporine, and retinoids as well as physical agents, such as ultraviolet light. For the most part these agents act by suppressing immune function. A topical immune response modifier, imiquimod has been shown to enhance the cutaneous immune response. Imiquimod has anti-viral and anti-tumor effects in animal models and has been approved for the topical treatment of external genital and perianal warts in humans. The biologic activity of imiquimod in part is due to its effect as a cytokine inducer. Preliminary data suggested that imiquimod could have an effect on Langerhans cells. In order to clarify this effect on Langerhans cells, we examined Langerhans cell morphology and migration in imiquimod-treated skin. The density of Ia + cells decreased 2 d after treatment, falling to approximately 43% by day 10. The Ia positive in cells remaining in the skin appeared larger and more dendritic suggesting an activated state. ATPase staining of epidermal sheet confirmed the decreased number of Langerhans cells. To clarify status of Langerhans cells, the activation of B7 was examined. Activation of B7-1 or B7-2 was not detected. Imiquimod, however, did enhance Langerhans cell migration from skin to draining lymph nodes. This enhanced Langerhans cell migration was also associated with an enhanced allergic contact hypersensitivity. These results suggest that the mechanism of modulation of immune response by imiquimod is in part due to effects on Langerhans cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10620129&dopt=Abstract imiquimod Aldara



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Nudging epidermal field cancerogenesis by imiquimod.

Uhoda I, Quatresooz P, Pierard-Franchimont C, Pierard GE.

Department of Dermatopathology, University Medical Center of Liege, Belgium.

BACKGROUND: The coexistence of malignancies close to each other on the skin has been occasionally reported. The concept of field cancerogenesis applies to such cases. Given the purported mechanism of action of imiquimod, it should not be surprising that this treatment could inhibit epidermal field cancerogenesis. AIM: To assess the effect of imiquimod applied twice weekly on incipient bowenoid changes disclosed in the vicinity of basal cell carcinomas. MATERIALS AND METHOD: Biopsies were taken before treatment and after 4-6 weeks and 12 weeks of imiquimod treatment. RESULTS: Large atypical bowenoid keratinocytes and dyskeratotic cells were cleared in time while factor-XIIIa-positive dermal dendrocytes appeared boosted and admixed with a brisk lymphocytic infiltration. CONCLUSION: Epidermal field cancerogenesis appears to be controlled by imiquimod. Dermal dendrocytes might play a pivotal role in this regression phenomenon. Copyright 2003 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12771486&dopt=Abstract imiquimod Aldara



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Prolonged imiquimod treatment and graft-versus-host reaction: histological mimicry in the skin infiltration pattern of the monocyte-macrophage-dendrocyte lineage.

Hermanns-Le T, Paquet P, Nikkels AF, Pierard-Franchimont C, Pierard GE.

Department of Dermatopathology, University Medical Center of Liege, Belgium.

Factor-XIIIa-positive dendrocytes belong to the monocyte-macrophage-dendrocyte (MMD) lineage which is considered to play a pivotal role in the skin response to the immune response modifier imiquimod. The same cells are also boosted in low-grade graft-versus-host reaction (GVHR) with skin manifestations. Both conditions are characterized by specific epidermal damage. The aim of the present study was to compare them using immunohistochemistry to identify MMD subsets and other inflammatory cells in the dermis. We compared 3 cases of long-term (4, 9 and 11 months) imiquimod topical applications on normal skin, 25 low-grade GVHR controlled by immunosuppressive therapy and 25 control cases with normal skin. Compared to the normal dermis, cells of the MMD lineage were considerably boosted in the dermis of GVHR and at the imiquimod-treated sites. By contrast, only minimal accumulations of lymphocytes and Langerhans cells were disclosed in the dermis. The pattern of dermal infiltration by MMD cells was similar in GVHR and after imiquimod treatment. However, intraindividual differences in densities were obvious irrespective of the skin condition. In conclusion, there is great mimicry in the MMD involvement in the dermis during low-grade GVHR and after chronic applications of imiquimod. Copyright 2003 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12771487&dopt=Abstract imiquimod Aldara



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Transient effect of topical treatment of cutaneous leishmaniasis with imiquimod.

Seeberger J, Daoud S, Pammer J.

Department of Dermatology and Venereology, Faculty of Medicine, University of Damascus, Syria.

BACKGROUND: Treatment of cutaneous leishmaniasis can be painful and protracted and cosmetic results are often unsatisfying. The immune modulator imiquimod has been reported to be suitable for the treatment of a variety of infectious skin diseases and neoplasias. OBJECTIVE: We investigated the efficacy of topical application of imiquimod in the treatment of old world leishmaniasis in a placebo-controlled prospective study. METHODS: Twelve patients were treated with imiquimod cream using a standard protocol, i.e. topical application three times a week, and a further three served as control group. RESULTS: Lesions of cutaneous leishmaniasis regressed within the first 2-4 weeks in 10 of the 12 patients, whereas in two patients no change was observed. However, after 8 weeks all lesions showed progression. CONCLUSION: Our results thus demonstrate that topical application of imiquimod alone is ineffective in treating old world cutaneous leishmaniasis. Further studies are required to demonstrate a possible benefit of imiquimod in combination with other, preferably orally administered medicines.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12839616&dopt=Abstract imiquimod Aldara



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Synthesis and structure-activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effects.

Isobe Y, Tobe M, Ogita H, Kurimoto A, Ogino T, Kawakami H, Takaku H, Sajiki H, Hirota K, Hayashi H.

Research Division, Discovery Research Laboratories II, Sumitomo Pharmaceuticals Co. Ltd., Konohana-ku, 554-0022, Osaka, Japan.

Recently we reported the adenine derivatives (2-4) as new interferon (IFN) inducers. In the present study, we conducted a detailed structure and activity relationship study of 4 and its related derivatives on IFN inducing activity. From this study, we found that compound 4 exhibited the most potent IFN inducing activity in vitro with a minimum effective concentration of 0.01 microM, and 4 also showed strong IFN-inducing activity at doses of more than 0.3mg/kg by oral administration in mice. This potency was 10-fold stronger than that of Imiquimod. Moreover, 4 did not cause emesis in ferrets even at doses as high as 10mg/kg, whereas, 80% of animals were emetic when orally administered with the same dose of Imiquimod. These results indicate that compound 4 is superior to Imiquimod with respect to efficacy and safety.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12901909&dopt=Abstract imiquimod Aldara



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Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod.

Schon M, Bong AB, Drewniok C, Herz J, Geilen CC, Reifenberger J, Benninghoff B, Slade HB, Gollnick H, Schon MP.

Department of Dermatology, Otto-von-Guericke-University, Magdeburg, Germany. schoenmargret web.de

BACKGROUND: The incidence of nonmelanoma skin cancer, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) is increasing, representing a major medical and economic problem. Imiquimod, a topical small-molecule immune response modifier, has shown efficacy toward BCC and actinic keratoses in clinical trials. Imiquimod acts both indirectly, via cytokine-mediated stimulation of cellular immune responses, and directly, through unknown mechanisms against tumor cells. We examined the mechanism by which imiquimod induces apoptosis in cancer cells. METHODS: Apoptosis was assessed by enzyme-linked immunosorbent assay, western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays in five SCC cell lines, HaCaT cells (a spontaneously immortalized human keratinocyte cell line), and normal keratinocytes treated with imiquimod, with its analog resiquimod, or with neither. Expression of death receptors, caspases, and cytochrome c in the apoptotic signaling cascade was analyzed using western blot and flow cytometric analyses. The functional relevance of imiquimod-induced cytochrome c release was assessed by transfection of HaCaT cells with Bcl-2. Apoptosis in BCCs in vivo was assessed by TUNEL assays of imiquimod-treated and untreated tumors from three patients. Differences between treated and untreated cells and tumors were determined using a two-tailed Student's t test. RESULTS: Imiquimod, but not resiquimod, induced apoptosis in all SCC cell lines and HaCaT cells. This induction involved activation of several caspases and Bcl-2-dependent cytosolic translocation of cytochrome c but was independent of the membrane-bound death receptors Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R1-R4 receptors, and tumor necrosis factor-R1 and -R2 receptors. Topical application of imiquimod to BCC tumors in vivo induced apoptosis. CONCLUSION: Imiquimod has the potential to induce apoptosis in skin cancer cells, possibly by circumventing mechanisms developed by malignant tumors to resist apoptotic signals.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12902443&dopt=Abstract imiquimod Aldara