Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Dermatology Therapeutics

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

  • Text
  • PDF
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

×

Figure 1

F8-VEGF-C and F8-VEGF-C156Ser fusion proteins retain antigen affinity and biological activity.

Options: View larger image (or click on image) Download as PowerPoint
F8-VEGF-C and F8-VEGF-C156Ser fusion proteins retain antigen affinity an...
(A) Schematic representation of the F8-VEGF-C fusion protein. (B) SDS-PAGE analysis of F8-VEGF-C (noncontiguous lanes on same gel) and F8-VEGF-C156Ser. Lanes show size ladder (L) and protein under nonreducing (N) or reducing (R) conditions. (C) Size-exclusion chromatograms of F8-VEGF-C and F8-VEGF-C156Ser. (D) Surface plasmon resonance analysis of F8-VEGF-C and F8-VEGF-C156Ser using an EDA-coated chip. (E) Western blot analysis of VEGFR-3–overexpressing PAE cells for VEGFR-2 and phosphorylated VEGFR-2 as well as VEGFR-3 and phosphorylated VEGFR-3. Molecular weight markers are indicated on the right. (F) Proliferation assay of human LECs after 72 hours of indicated treatment (n = 5 wells per condition, 1-way ANOVA with Bonferroni post test, 1 of 3 similar experiments shown). (G) Sprouting assay of human LECs, counting sprouts formed per LEC-coated bead (n = 5 wells per condition, 1-way ANOVA with Bonferroni post test, 1 of 3 similar experiments shown). (H) Quantification of LYVE-1+ area on stained diaphragm from pups (see I, n = 3–4 animals, 2-tailed Student’s t test, 1 of 2 similar experiments shown). (I) Whole-mount immunofluorescence staining for CD31 (red) and LYVE-1 (green) on diaphragms of pups having received 5 injections of PBS or F8-VEGF-C. Scale bar: 100 μm. Data represent mean ± SD. *P < 0.05, ***P < 0.001.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts