Publications by authors named "Edwin Florencia"

10 Publications

  • Page 1 of 1

Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers.

Br J Clin Pharmacol 2021 Jul 22. Epub 2021 Jul 22.

Centre for Human Drug Research, Leiden, the Netherlands.

Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.

Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 10 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.

Results: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24-hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)-6, IL-8 and tumour necrosis factor response followed by IL-1β, IL-10 and interferon-γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.

Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14999DOI Listing
July 2021

Topical anti-microbial peptide omiganan recovers cutaneous dysbiosis but does not improve clinical symptoms in patients with mild-to-moderate atopic dermatitis in a phase 2 randomized controlled trial.

J Am Acad Dermatol 2020 Sep 30. Epub 2020 Sep 30.

Centre for Human Drug Research, Leiden, the Netherlands; Department of Dermatology Erasmus Medical Centre, Rotterdam, the Netherlands.

Background: Dysbiosis and colonization with Staphylococcus aureus is considered to play an important role in the pathogenesis of atopic dermatitis (AD). Recovering this dysbiosis may improve AD symptoms. Omiganan is a synthetic indolicidin analogue antimicrobial peptide with activity against S. aureus and could be a viable new treatment option for AD.

Objective: To explore the tolerability, clinical efficacy and pharmacodynamics of omiganan in mild-to-moderate AD.

Methods: Eighty patients were randomized to omiganan 1%, 1.75%, 2.5% or vehicle twice daily for 28 days on all lesions. Weekly visits included clinical scores, and microbiological and pharmacodynamic assessments of one 'target lesion'.

Results: In all omiganan treatment groups dysbiosis was recovered by reducing Staphylococcus abundance and increasing diversity. A reduction of cultured S. aureus was observed in all omiganan treatment groups, with a significant reduction for omiganan 2.5% compared to vehicle (-93.5%, 95%CI=-99.2%/-28.5% p=0.02). No significant clinical improvement was observed.

Conclusion: Topical administration of omiganan twice daily for up to 28 days in patients with mild-to-moderate AD led to a recovery of dysbiosis, but without clinical improvement. Therefore, a mono-treatment that selectively targets the microbiome does not appear to be a successful treatment strategy in mild-to-moderate AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.08.132DOI Listing
September 2020

Lesional Inflammatory Profile in Hidradenitis Suppurativa Is Not Solely Driven by IL-1.

J Invest Dermatol 2020 07 17;140(7):1463-1466.e2. Epub 2020 Feb 17.

Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2020.01.023DOI Listing
July 2020

Omiganan Enhances Imiquimod-Induced Inflammatory Responses in Skin of Healthy Volunteers.

Clin Transl Sci 2020 05 13;13(3):573-579. Epub 2020 Feb 13.

Centre for Human Drug Research, Leiden, The Netherlands.

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%-30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%-2.83; P = 0.02). Interferon regulatory factor-driven and NFκB-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFNɣ), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.12741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214655PMC
May 2020

Comprehensive, Multimodal Characterization of an Imiquimod-Induced Human Skin Inflammation Model for Drug Development.

Clin Transl Sci 2018 11 3;11(6):607-615. Epub 2018 Jul 3.

Department of Dermatology Erasmus Medical Centre, Rotterdam, The Netherlands.

Imiquimod (IMQ) is often used as a topical challenge agent to provoke local skin inflammation. The objective of this study was to develop and refine a rapid, temporary, and reversible human skin inflammation model with IMQ for application in clinical drug development. A randomized, vehicle-controlled, open-label, dose-ranging study was conducted in 16 healthy male subjects. IMQ (5 mg) was applied once daily for 72 hours under occlusion to intact skin (n = 8) or tape stripped (TS) skin (n = 8). Although IMQ alone induced limited effects, TS+IMQ treatment showed larger responses in several domains, including erythema and perfusion (P < 0.0001), mRNA expression of inflammatory markers (P < 0.01), and inflammatory cell influx compared with vehicle. In conclusion, a rapid, human IMQ skin inflammation challenge model was successfully developed with a clear benefit of TS prior to IMQ application. Future interaction studies will enable proof-of-pharmacology of novel compounds targeting the innate immune system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cts.12563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226121PMC
November 2018

Surgical Denervation in the Imiquimod-Induced Psoriasiform Mouse Model.

Methods Mol Biol 2017 ;1559:75-81

Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Psoriasis is a chronic inflammatory skin disease with a prevalence of 2-3 %. It appears to result from a combination of genetic and environmental factors, but the precise pathogenesis is still unknown. Neurogenic inflammation is involved in psoriasis pathogenesis as well, but the role of neurogenic factors is currently unclear. Molecular studies often involve material obtained from patients. However, many questions and especially experimental manipulations are not suited for study in humans. Imiquimod application on mouse skin leads to immune cell infiltration, inflammation with intense redness, epidermal thickening, and scaling that jointly greatly resembles human psoriasis. Here we describe the use of surgical denervation in the imiquimod-induced psoriasiform model, to study the role of skin innervation and neuropeptides in the pathogenesis of psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-4939-6786-5_6DOI Listing
January 2018

MCPIP1 RNase Is Aberrantly Distributed in Psoriatic Epidermis and Rapidly Induced by IL-17A.

J Invest Dermatol 2016 08 12;136(8):1599-1607. Epub 2016 May 12.

Translational Immunology, Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain. Electronic address:

ZC3H12A, which encodes the RNase monocyte chemotactic protein-induced protein 1 (MCPIP1), is up-regulated in psoriatic skin and reduced to normal levels after clinical treatments with anti-IL-17A/IL-17R neutralizing antibodies. In IL-17A-stimulated keratinocytes, MCPIP1 is rapidly increased at the transcript and protein levels. Also, IL-17A was found to be the main inducer of ZC3H12A expression in keratinocytes treated with supernatants derived from a Streptococcus pyogenes-activated psoriatic ex vivo model based on the co-culture of psoriatic cutaneous lymphocyte-associated antigen (CLA(+)) T cells and lesional epidermal cells. Moreover, MCPIP1 was aberrantly distributed in the suprabasal layers of psoriatic epidermis. In psoriatic samples, IL-17A-stimulated epidermal cell suspensions showed an increased MCPIP1 expression, especially in the mid-differentiated cellular compartment. The knockdown of ZC3H12A showed that this RNase participates in the regulation of the mRNAs present in suprabasal differentiated keratinocytes. Furthermore, JAK/STAT3 inhibition prevented the IL-17A-dependent induction of MCPIP1. In the mouse model of imiquimod-induced psoriasis, Zc3h12a expression was abrogated in Il17ra(-/-) mice. These results support the notion that IL-17A-mediated induction of MCPIP1 is involved in the regulation of local altered gene expression in suprabasal epidermal layers in psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2016.04.030DOI Listing
August 2016

IL-4 Downregulates IL-1β and IL-6 and Induces GATA3 in Psoriatic Epidermal Cells: Route of Action of a Th2 Cytokine.

J Immunol 2015 Aug 13;195(4):1744-52. Epub 2015 Jul 13.

Department of Dermatology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands; Department of Immunology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, the Netherlands;

Clinical improvement of psoriasis induced by IL-4 treatment has been ascribed to changes in dermal inflammatory cells, such as activation of Th2 cells and tolerization of dendritic cells by suppressing IL-23 production. The pathologic epidermal alterations in psoriatic lesional skin include increased epidermal expression of IL-1β, IL-6, S100A7, and human β-defensin 2 (hBD2) and a downregulated expression of the epidermal transcription factor GATA3. Effects of IL-4 on the epidermal compartment of psoriasis lesions were not previously investigated. Therefore, we investigated whether IL-4 directly affects abovementioned psoriatic markers in the epidermal compartment. We cultured freshly isolated psoriatic epidermal cells, whole psoriatic and healthy skin biopsies, human keratinocytes and Langerhans cells with IL-4. The secretion of IL-1β and IL-6 by psoriatic epidermal cells was inhibited by IL-4 via transcriptional and posttranscriptional mechanisms, respectively. In normal skin, IL-4 inhibited IL-1β- and IL-17A-induced hBD2 expression in vitro. In addition, IL-4 reduced the protein expression of hBD2 in psoriatic skin biopsies and induced phospho-STAT6 protein. Epidermal GATA3 mRNA and protein were significantly upregulated by IL-4 in epidermal cells and keratinocytes. Our data argue that IL-4 improves psoriasis not only via modification/induction of Th2 cells and type II dendritic cells, but also via direct inhibition of inflammatory cytokines in resident IL-4R-expressing epidermal cells and thereby alters the psoriatic skin phenotype toward a healthy skin phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1401740DOI Listing
August 2015

GATA3 expression is decreased in psoriasis and during epidermal regeneration; induction by narrow-band UVB and IL-4.

PLoS One 2011 17;6(5):e19806. Epub 2011 May 17.

Department of Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions.Psoriatic lesional skin showed decreased GATA3 mRNA and protein expression compared to non-lesional skin. GATA3 expression was also markedly decreased in inflamed skin of mice with a psoriasiform dermatitis induced with imiquimod. Tape-stripping of non-lesional skin of patients with psoriasis, a standardized psoriasis-triggering and skin regeneration-inducing technique, reduced the expression of GATA3. In wounded skin of mice, low GATA3 mRNA and protein expression was detected. Taken together, GATA3 expression is downregulated under regenerative and inflammatory hyperproliferative skin conditions. GATA3 expression could be re-induced by successful narrow-band UVB treatment of both human psoriasis and imiquimod-induced psoriasiform dermatitis in mice. The prototypic Th2 cytokine IL-4 was the only cytokine capable of inducing GATA3 in skin explants from healthy donors. Based on these findings we argue that GATA3 serves as a key regulator in psoriatic inflammation, keratinocyte hyperproliferation and skin barrier dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096641PMC
September 2011

Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.

J Immunol 2009 May;182(9):5836-45

Department of Dermatology, Erasmus Medical Center, Rotterdam, The Netherlands.

Topical application of imiquimod (IMQ), a TLR7/8 ligand and potent immune activator, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. Recently, a crucial role was proposed for the IL-23/IL-17 axis in psoriasis. We hypothesized that IMQ-induced dermatitis in mice can serve as a model for the analysis of pathogenic mechanisms in psoriasis-like dermatitis and assessed its IL-23/IL-17 axis dependency. Daily application of IMQ on mouse back skin induced inflamed scaly skin lesions resembling plaque type psoriasis. These lesions showed increased epidermal proliferation, abnormal differentiation, epidermal accumulation of neutrophils in microabcesses, neoangiogenesis, and infiltrates consisting of CD4(+) T cells, CD11c(+) dendritic cells, and plasmacytoid dendritic cells. IMQ induced epidermal expression of IL-23, IL-17A, and IL-17F, as well as an increase in splenic Th17 cells. IMQ-induced dermatitis was partially dependent on the presence of T cells, whereas disease development was almost completely blocked in mice deficient for IL-23 or the IL-17 receptor, demonstrating a pivotal role of the IL-23/IL-17 axis. In conclusion, the sole application of the innate TLR7/8 ligand IMQ rapidly induces a dermatitis closely resembling human psoriasis, critically dependent on the IL-23/IL-17 axis. This rapid and convenient model allows further elucidation of pathogenic mechanisms and evaluation of new therapies in psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.0802999DOI Listing
May 2009
-->