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

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 2

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mAb 146B7 inhibits protection of apoptosis by IL-15. Human PBMCs were in...
mAb 146B7 inhibits protection of apoptosis by IL-15. Human PBMCs were incubated with IL-15 (5 ng/ml) in culture medium alone (filled squares) or in combination with 10 μg/ml mAb 146B7 (open circles) or with 10 μg/ml isotype control antibody (filled triangles) for 5 days. Apoptosis was measured using annexin V conjugated with FITC and PI. Live (a and d), early (b and e), and late (c and f) apoptotic cells were defined by annexin V-FITCnegPIneg, annexin V-FITCposPIneg, and annexin V-FITCposPIpos staining by flow cytometry, respectively. Representative data of three individual experiments with six different PBMC donors are shown. (a–c) mAb 146B7 inhibits IL-15–induced survival of monocytes. (d–f) No significant differences in comparison were found in the fraction of live and apoptotic T cells. *P < 0.05, mAb 146B7 versus no antibody treatment. **P < 0.005, mAb 146B7 versus no antibody treatment, and mAb 146B7 versus anti-KLH.