Self-administered Topical 5% Imiquimod Cream for External Anogenital Warts

Edwards, Libby

doi:10.1001/archderm.134.1.25

Cited by 509 publications

(395 citation statements)

References 17 publications

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“…In independent studies, these TLR7 ligands have been demonstrated to exhibit better efficiency in female than male patients, and there have been several speculations about the underlying mechanism, such as, for example, sex-dependent skin resorption of the drug in female patients (65)(66)(67). Our results link the improved clinical efficacy directly with a sex-dependent IFN-␣ induction and consequently higher antiviral activity in female patients.…”

Section: Discussionmentioning

confidence: 52%

TLR7 Ligands Induce Higher IFN-α Production in Females

Berghöfer

Frommer

Haley

et al. 2006

The Journal of Immunology

407

329

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IFN-α exercises multiple immune modulatory and antiviral activities and has been suggested to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) release IFN-α upon TLR7 and TLR9 ligation. With respect to the nine times higher incidence of SLE in women and the clinical use of synthetic TLR ligands as novel immune adjuvants, we analyzed IFN-α and TNF-α production in healthy human individuals. Blood samples were incubated with synthetic TLR7 and TLR9 ligands. In three independent groups (n1 = 120, n2 = 101, and n3 = 123), analysis revealed a capacity of female PBLs to produce significantly higher IFN-α levels after TLR7 stimulation (p1 < 0.0000001, p2 < 0.0000001, and p3 < 0.0001) compared with male PBLs. In contrast, no sex differences were evident after TLR9 stimulation. TNF-α production after TLR7 stimulation and also total pDC numbers were not different between females and males. X-inactivation escape of the TLR7 gene was investigated in monoclonal B cell lines and, independently, in pDCs after cell sorting and single-cell picking, indicating regular silencing of one TLR7 allele in females. Additionally, exogenous 17β-estrogen and estrogen receptor antagonism did not indicate a significant role on TLR7-induced IFN-α production. Our data reveal for the first time a profound sex-dependent pathway of TLR7-induced IFN-α with higher production in females. These findings may explain the higher prevalence of SLE in females and the reported decreased therapeutic efficacy of synthetic TLR7 ligands in male individuals.

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Section: Discussionmentioning

confidence: 52%

TLR7 Ligands Induce Higher IFN-α Production in Females

Berghöfer

Frommer

Haley

et al. 2006

The Journal of Immunology

407

329

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“…Loxoribine, the more potent guanosine analog, shows anti-viral and anti-tumor activity in murine animal models and has entered phase I clinical trials [19][20][21]. Based on their effective anti-viral and anti-tumor activities in various animal models, the imidazoquinolines imiquimod and resiquimod (R-848) have been approved for treatment of genital warts caused by human papillomavirus, and the more potent compound R-848 is anticipated as a treatment of recurring genital herpes [22][23][24][25]. The finding that human and murine TLR7 [12] and human TLR8 [13] confer responsiveness to R-848 supports the idea that synthetic adjuvants may signal via TLR and thus mimic their as-yet-unknown natural ligands.…”

Section: Introductionmentioning

confidence: 99%

The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily

Heil¹,

Ahmad-Nejad²,

Hemmi³

et al. 2003

Eur J Immunol

505

379

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Loxoribine (7-allyl-7,8-dihydro-8-oxo-guanosine) acts as synthetic adjuvant in anti-tumor responses. Here we first demonstrate that loxoribine activates cells of the innate immune system selectively via the Toll-like receptor (TLR) 7/MyD88-dependent signaling pathway. TLR7-and MyD88-deficient immune cells fail to proliferate or produce cytokines in response to loxoribine, and genetic complementation of TLR7-deficient cells with murine or human TLR7 confers responsiveness. Subsequently we show that cellular activation by loxoribine and resiquimod (R-848), a stimulus for TLR7 and TLR8, depends on acidification and maturation of endosomes and targets MyD88 to vesicular structures with lysosomal characteristics. This mode of TLR7 and TLR8 action resembles CpG-DNA-driven TLR9 activation. We thus conclude that TLR7, 8 and 9 form a functional subgroup within the TLR family that recognizes pathogen-associated molecular patterns in endosomal/lysosomal compartments.

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“…These compounds have been previously shown to have potent antiviral and antitumor properties in animals, and imiquimod has recently been indicated for treatment of genital warts caused by papilloma virus infection in humans (1)(2)(3)(4)(5)(6). In addition to their previously demonstrated effectiveness in inducing cytokine secretion by monocytes and dendritic cells, the imidazoquinolines have been recently shown to possess potent activating properties for B lymphocytes (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Molecular Mechanisms of B Lymphocyte Activation by the Immune Response Modifier R-848

Bishop

Hsing²,

Hostager³

et al. 2000

The Journal of Immunology

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The imidazoquinoline R-848, originally identified as a highly effective antiviral agent, has recently been shown to be capable of potent B lymphocyte activation. The B cell-activating properties of R-848 are strikingly similar to the effects of the CD40 ligand CD154. The present study demonstrates that this similarity extends to the intracellular signaling pathways triggered by the compound, although both overlapping and distinct mechanisms of signaling were seen. Like CD40 ligation, R-848 stimulated activation of the stress-activated protein kinases c-Jun kinase and p38 and activated the NF-κB family of transcription factors. Both R-848- and CD40-mediated B cell differentiation were dependent upon NF-κB activation, although the relative importance of individual NF-κB family members appeared to differ between R-848- and CD40-mediated signals. Both signals were partially dependent upon induction of TNF-α and IL-6, and the cytoplasmic adaptor molecule TNF receptor-associated factor 2 is involved in both R-848- and CD40-mediated differentiation.

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Self-administered Topical 5% Imiquimod Cream for External Anogenital Warts

Cited by 509 publications

References 17 publications

TLR7 Ligands Induce Higher IFN-α Production in Females

TLR7 Ligands Induce Higher IFN-α Production in Females

The Toll‐like receptor 7 (TLR7)‐specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily

Molecular Mechanisms of B Lymphocyte Activation by the Immune Response Modifier R-848

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