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Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation
Simon Schwager, … , Dario Neri, Michael Detmar
Simon Schwager, … , Dario Neri, Michael Detmar
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e124850. https://doi.org/10.1172/jci.insight.124850.
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Research Article Dermatology Therapeutics

Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation

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Abstract

VEGF-C is an important mediator of lymphangiogenesis and has been shown to alleviate chronic inflammation in a variety of disease models. In this study, we investigated whether targeted delivery of VEGF-C to sites of inflammation and site-specific activation of lymphatic vessels would represent a clinically feasible strategy for treating chronic skin inflammation. To this end, we generated a fusion protein consisting of human VEGF-C fused to the F8 antibody (F8-VEGF-C), which is specific for the alternatively spliced, angiogenesis-marking extradomain A (EDA) of fibronectin. In two mouse models of psoriasis-like skin inflammation, mediated by transgenic VEGF-A overexpression or repeated application of imiquimod, intravenous treatment with F8-VEGF-C but not with untargeted VEGF-C significantly reduced ear skin edema and was as effective as the clinically used TNF-α receptor-Fc fusion protein (TNFR-Fc). Treatment with F8-VEGF-C led to a marked expansion of lymphatic vessels in the inflamed skin and significantly improved lymphatic drainage function. At the same time, treatment with F8-VEGF-C significantly reduced leukocyte numbers, including CD4+ and γδ T cells. In sum, our results reveal that targeted delivery of VEGF-C and site-specific induction of lymphatic vessels represent a potentially new and promising approach for the treatment of chronic inflammatory diseases.

Authors

Simon Schwager, Silvana Renner, Teresa Hemmerle, Sinem Karaman, Steven T. Proulx, Roman Fetz, Alexandra Michaela Golding-Ochsenbein, Philipp Probst, Cornelia Halin, Dario Neri, Michael Detmar

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Figure 4

F8-VEGF-C but not KSF-VEGF-C causes lymphatic expansion and accelerates edema resolution in imiquimod-induced inflammation.

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F8-VEGF-C but not KSF-VEGF-C causes lymphatic expansion and accelerates ...
(A) Schematic of inflammation study time course and treatment schedule. (B) Ear thickness represented as change compared with ear thickness on day 1 (n = 9 animals per group, 2-way ANOVA with Bonferroni post test; P values noted by an asterisk show comparisons between F8-VEGF-C and KSF-VEGF-C and those noted by pound signs show comparisons between F8-VEGF-C and SIP-F8). (C) Immunofluorescence images of ears from mice that received SIP-F8, KSF-VEGF-C, or F8-VEGF-C stained for LYVE-1 (green), MECA-32 (red), and DAPI (blue). Scale bar: 100 μm. (D) Quantification of lymphatic vessel area (expressed as percentage of analyzed area, n = 6–9 animals per group, 1-way ANOVA with Games-Howell post test). (E) Number of lymphatic vessels in inflamed ears of mice that received the indicated treatment (normalized to basement membrane length, n = 6–9 animals per group, 1-way ANOVA with Bonferroni post test). (F) Quantification of blood vessel area in inflamed ears of mice that received the indicated treatment (expressed as percentage of analyzed area, n = 6–9 animals per group, 1-way ANOVA with Bonferroni post test). (G) Number of blood vessels in inflamed ears (normalized to basement membrane, n = 6–9 animals per group). Data represent mean ± SD. BM, basement membrane. *P < 0.05, **P < 0.01, ***P < 0.001.

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