Apilimod inhibits the production of IL-12 and IL-23 and reduces dendritic cell infiltration in psoriasis

• Published in: PloS one 2012-04, Vol.7 (4), p.e35069-e35069
• Main Authors: Wada, Yumiko, Cardinale, Irma, Khatcherian, Artemis, Chu, John, Kantor, Aaron B, Gottlieb, Alice B, Tatsuta, Noriaki, Jacobson, Eric, Barsoum, James, Krueger, James G
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adolescent; Adult; Aged; Antigens, CD - immunology; Autoimmune diseases; B cells; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Biology; Biomarkers; CD11c antigen; CD3 antigen; Cell Movement - drug effects; Cell Movement - immunology; Chemical synthesis; Chemokines; Cytokines; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dermatitis; Dermatology; Dermis; Eosinophils; Eosinophils - drug effects; Eosinophils - immunology; Epidermis; Female; Gene expression; Helper cells; Histology; Humans; Hyperplasia; Immunomodulation; Infiltration; Inflammation; Inflammatory diseases; Interleukin 10; Interleukin 12; Interleukin 23; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Interleukin-12 - immunology; Interleukin-23 - antagonists & inhibitors; Interleukin-23 - biosynthesis; Interleukin-23 - immunology; Laboratories; Leishmania major; Lesions; Leukocytes; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Medical treatment; Medicine; Middle Aged; Morpholines - administration & dosage; Morpholines - therapeutic use; Neutrophils - drug effects; Neutrophils - immunology; Oral administration; Pathogenesis; Patients; Pharmaceuticals; Psoriasis; Psoriasis - drug therapy; Psoriasis - immunology; Psoriasis - pathology; Skin; Skin - drug effects; Skin - immunology; Skin - pathology; Skin diseases; T cells; Th1 Cells - drug effects; Th1 Cells - immunology; Th17 Cells - drug effects; Th17 Cells - immunology; Transcription factors; Triazines - administration & dosage; Triazines - therapeutic use; White blood cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035069

Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces T(H)17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70 mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of T(H)1 and T(H)17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c(+) dendritic cells and CD3(+) T cells was seen, with a greater decrease in the CD11c(+) population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of T(H)1- and T(H)17-mediated inflammatory diseases.