title: Resolution of psoriasis by a leukocyte-targeting bacterial protein in a humanized mouse model.
abstract: Psoriasis is a very common chronic skin disease, affecting 2-3% of the world's population or more than 125 million individuals worldwide. The characteristic lesion of psoriasis is due to rapid proliferation and shortened transition of keratinocytes through the epidermis. Proinflammatory white blood cells (WBCs) migrate into the psoriatic plaques, and the pathogenic cytokine environment causes the changes in keratinocyte proliferation and differentiation. Enhanced migration of WBCs is due to the upregulation and activation of adhesion molecules such as leukocyte function antigen-1 (LFA-1), which binds intercellular adhesion molecule-1 (ICAM-1) on endothelial cells. Targeting LFA-1 and preventing interaction with ICAM-1 has proven an effective strategy for treating psoriasis. We show here that a natural leukocyte-targeting bacterial protein (leukotoxin (LtxA)) that binds LFA-1 can inhibit proliferation of activated WBCs from psoriasis patients and demonstrates significant therapeutic efficacy in a psoriasis xenograft transplantation model. In ex vivo studies, LtxA preferentially targeted proinflammatory WBC subtypes, including activated CD25(+) T cells and CD14(+)CD16(+) monocytes. LFA-1 has been shown to have a significant role in the pathogenesis of numerous autoimmune and inflammatory diseases, and we propose that LtxA may be a highly effective agent for treating these diseases.
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Stenderup
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rosada
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Dam
authors.forename: Erica
authors.initials: E
authors.lastname: Salerno
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Belinka
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kachlany
mesh_terms: D000328:Adult; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry*; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004817:Epidermis / Q000378:metabolism; D005098:Exotoxins / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D019169:Jurkat Cells; D015603:Keratinocytes / Q000166:cytology; D007962:Leukocytes / Q000166:cytology*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011565:Psoriasis / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D017452:Receptors, IgG / Q000096:biosynthesis
chemical_list: D001426:Bacterial Proteins; D005098:Exotoxins; D053645:Interleukin-2 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; D016169:Lymphocyte Function-Associated Antigen-1; D017452:Receptors, IgG; C018579:leukotoxin; D018799:Intercellular Adhesion Molecule-1