Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model.
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.
Villadsen
Louise S
LS
Department of Dermatology, Gentofte University Hospital, Copenhagen, Denmark.
Schuurman
Janine
J
Beurskens
Frank
F
Dam
Tomas N
TN
Dagnaes-Hansen
Frederik
F
Skov
Lone
L
Rygaard
Jorgen
J
Voorhorst-Ogink
Marleen M
MM
Gerritsen
Arnout F
AF
van Dijk
Marc A
MA
Parren
Paul W H I
PW
Baadsgaard
Ole
O
van de Winkel
Jan G J
JG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018604:Epitope Mapping; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology / Q000502:physiology*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D019394:Ki-67 Antigen; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2