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-gamma, TNF-alpha, 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 alpha, beta, gamma complex. This antibody effectively blocked IL-15-induced T cell proliferation and monocyte TNF-alpha 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 Dagnaes-Hansen, Lone Skov, Jorgen 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 112 Issue 10 Pg. 1571-80 (Nov 2003) ISSN: 0021-9738 [Print] United States
• PMID: 14617758 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• IL15RA protein, human
• Il15ra protein, mouse
• Interleukin-15
• Ki-67 Antigen
• Receptors, Interleukin-15
• Receptors, Interleukin-2

Topics

• Animals
• Antibodies, Monoclonal (immunology, metabolism)
• Antigens, CD (immunology, metabolism)
• Disease Models, Animal
• Epitope Mapping
• Humans
• Interleukin-15 (immunology, physiology)
• Ki-67 Antigen (metabolism)
• Mice
• Mice, SCID
• Mice, Transgenic
• Psoriasis (immunology, pathology, therapy)
• Receptors, Interleukin-15
• Receptors, Interleukin-2 (immunology, metabolism)
• Skin Transplantation
• T-Lymphocytes (immunology, metabolism)
• Transplantation, Heterologous