Microarray analysis of aberrant gene expression in actinic keratosis: effect of the Toll-like receptor-7 agonist imiquimod

Torres, Abel; Storey, Leslie; Anders, Makala; Miller, Richard L.; Bulbulian, Barbara J; Jin, Jizhong; Raghavan, Shalini; Lee, J.; Slade, Herbert B.; Birmachu, Woubalem

doi:10.1111/j.1365-2133.2007.08218.x

Cited by 24 publications

(18 citation statements)

References 72 publications

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“…This is particularly of interest for a TLR7 agonist-based vaccine, as there is precedence for the induction of TLR7 expression in several cell types, such as DCs and even keratinocytes, after Type I IFN stimulation. 47 Indeed, we have observed a dramatic up-regulation of TLR7 expression in the dLN of mice injected subcutaneously with recombinant IFN␣ (J.Z.O. and R.M.K., unpublished results, June 2010).…”

Section: Tlr7-elicited Cd8 T-cell Response 3035mentioning

confidence: 89%

TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway

Kurche

Burchill

et al. 2011

Blood

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Conjugation of TLR agonists to protein or peptide antigens has been demonstrated in many studies to be an effective vaccine formula in inducing cellular immunity. However, the molecular and cellular mediators involved in TLR-induced immune responses have not been carefully examined. In this study, we identify Type I IFN and IL-12 as critical mediators of crosspriming induced by a TLR7 agonistantigen conjugate. We demonstrate that TLR7-driven cross-priming requires both Type I IFN and IL-12. Signaling through the IFN-␣␤R was required for the timely recruitment and accumulation of activated dendritic cells in the draining lymph nodes. Although IL-12 was indispensable during cross-priming, it did not regulate DC function. Therefore, the codependency for these 2 cytokines during TLR7-induced cross-priming is the result of their divergent effects on different celltypes. Furthermore, although dermal and CD8␣ ؉ DCs were able to cross-prime CD8 ؉ T cells, Langerhans cells were unexpectedly found to potently cross-present antigen and support CD8 ؉ T-cell expansion, both in vitro and in vivo. Collectively, the data show that a TLR7 agonistantigen conjugate elicits CD8 ؉ T-cell responses by the coordinated recruitment and activation of both tissue-derived and lymphoid organ-resident DC subsets through a Type I IFN and IL-12 codependent mechanism. (Blood. 2011;118(11): 3028-3038) IntroductionActivation of the innate immune system is a prerequisite to initiating adaptive immune responses. A major pathway eliciting these responses is the recognition of foreign bodies through Toll-like receptors (TLR), which results in the activation of antigen presenting cells (APC) and the production of a variety of proinflammatory mediators. 1 Previously, we showed that conjugation of a synthetic agonist targeting TLR7 to protein antigens results in a highly immunogenic vaccine that potently generates protective CD8 ϩ T-cell responses. 2 TLR7 is an intracellular receptor that recognizes single-stranded RNA molecules and detects RNA viruses such as the influenza virus. Stimulation of TLR7 has been shown in both mice and humans to result in vigorous production of multiple pro-inflammatory cytokines, including Type I IFN and IL-12. 3 The induction of Type I IFN and IL-12 is of particular interest given abundant evidence in the literature establishing these 2 cytokines as critical mediators of CD8 ϩ T-cell activation. 4,5 Type I IFN comprises a group of various IFN proteins, notably IFN␣ and IFN␤. IFNs are induced primarily during viral infections and have been shown to promote natural killer (NK), Type I helper T-cell (Th1), and CTL responses, 4 which are critical to combat viral infections through the elimination of virus-infected cells. Similarly, IL-12 also promotes the development of Th1 and CTL-mediated immunity. [6][7][8] However, the production of IL-12 is primarily associated with bacterial and parasitic infections. 7,9 The role of IL-12 during viral infections remains unclear as some reports indicate that CD8 ϩ T-cell responses elicit...

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Section: Tlr7-elicited Cd8 T-cell Response 3035mentioning

confidence: 89%

TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway

Kurche

Burchill

et al. 2011

Blood

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“…If DNA damage results in inhibition of apoptosis of actinically damaged cells, further derangements might accumulate, resulting in the development of squamous cell carcinoma. Torres et al [112] examined the changes in gene expression occurring in sun-exposed nonlesional skin and in AK lesions. They found that imiquimod treatment was associated with partial or total reversal of the aberrant expression of some genes in AK, thereby demonstrating the ability of imiquimod to prevent the development of cancer.…”

Section: Current Use Of Tlr7/8 Ligands In Cancer Treatment and Cancermentioning

confidence: 99%

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

et al. 2008

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After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

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“…8 Treatment of AKs with imiquimod increases expression of genes associated with dendritic cell, macrophage, T-cell, and natural killer cell activation 9 ; down-regulates antiapoptotic genes 10 ; and reverses aberrant expression of some genes observed in AKs. 11 In addition to treating clinically apparent lesions, topical treatment with imiquimod can reveal and clear subclinical lesions. Imiquimod 5% cream is approved to treat AKs of the face or balding scalp using dosing regimens of 23/wk for a single 16-week course in the United States 12,13 and 33/wk for two sequential 4-week cycles separated by a 4-week, no-treatment interval in Europe.…”

mentioning

confidence: 99%

Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: Results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles

Hanke

Beer

Stockfleth

et al. 2010

Journal of the American Academy of Dermatology

138

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Microarray analysis of aberrant gene expression in actinic keratosis: effect of the Toll-like receptor-7 agonist imiquimod

Abstract: The data show that profound gene expression changes occur in sun-exposed, nonlesional skin which progress further in AK lesions. The data also suggest that imiquimod may play a role in normalizing gene expression and cellular morphology in sun-damaged skin.

Cited by 24 publications

References 72 publications

TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway

TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: Results of two placebo-controlled studies of daily application to the face and balding scalp for two 3-week cycles

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