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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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Article Autoimmunity Article has an altmetric score of 12

Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model

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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 7

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A recent paper by Dubois et al. (40) provided new insight in the mechani...
A recent paper by Dubois et al. (40) provided new insight in the mechanism of action of IL-15. The formation of IL-15/IL-15Rα complexes on cell surfaces enables transendosomal recycling of IL-15, leading to persistence of surface-bound IL-15 (a). IL-15/IL-15Rα complexes may induce signaling via IL-15Rβ− and γ-chains expressed on the same cell in cis (b) or expressed on a distinct cell in trans (c). Antibody 146B7 binds at the interaction site of IL-15 with the γ-chain (d) and may effectively block signaling through the γ-chain both in cis and in trans (e).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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