Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model
Louise S. Villadsen, … , Ole Baadsgaard, Jan G.J. van de Winkel
Louise S. Villadsen, … , Ole Baadsgaard, Jan G.J. van de Winkel
Published November 15, 2003
Citation Information: J Clin Invest. 2003;112(10):1571-1580. https://doi.org/10.1172/JCI18986.
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Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model

Abstract

Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-γ, TNF-α, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAb’s using human immunoglobulin-transgenic mice. One of the IL-15–specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor α, β, γ complex. This antibody effectively blocked IL-15–induced T cell proliferation and monocyte TNF-α release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15–specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.

Authors

Louise S. Villadsen, Janine Schuurman, Frank Beurskens, Tomas N. Dam, Frederik Dagnæs-Hansen, Lone Skov, Jørgen Rygaard, Marleen M. Voorhorst-Ogink, Arnout F. Gerritsen, Marc A. van Dijk, Paul W.H.I. Parren, Ole Baadsgaard, Jan G.J. van de Winkel

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Figure 1

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Recognition of receptor-bound IL-15 by mAb 146B7 and inhibition of IL-15...
Recognition of receptor-bound IL-15 by mAb 146B7 and inhibition of IL-15–induced effects. (a) Biotinylated mAb 146B7 (filled squares) showed dose-dependent binding to IL-15 bound to IL-15Rα, which was coated onto an ELISA plate, whereas biotinylated 404E4 (filled triangles) did not show binding. Polyclonal huIgG1 (open squares) served as a control. This experiment was repeated two times, yielding similar results. (b) Dose-dependent binding of biotinylated mAb 146B7 (filled squares) to IL-15 bound to Raji lymphoma cells expressing IL-15Rα was shown by flow cytometry. Polyclonal huIgG1 (open squares) was used as a control. This experiment was repeated five times, yielding similar results. MFI, mean fluorescence intensity. (c) Effect of mAb 146B7 on IL-15–induced proliferation. Human PBMCs were incubated with IL-15 (12.5 ng/ml) in combination with mAb 146B7 (filled squares), mAb 404E4 (filled inverted triangles), or with huIgG1 (open squares) for 72 hours. BrdU incorporation was measured to assay proliferation. Representative data of 9 individual experiments are shown. (d) mAb 146B7 inhibits IL-15– but not IL-2–induced TNF-α production. Human PBMCs were incubated with IL-15 (0, 25, 100 ng/ml) or with IL-2 (100 ng/ml) in combination with mAb 146B7 at various concentrations for 72 hours. The amounts of TNF-α produced were measured by ELISA. A representative experiment from a series of 11 experiments is shown.