ABSTRACT
BACKGROUND: Atopic dermatitis (AD) is a chronic disease with a Th2-type-cytokine dominant profile. Several cytokines and related peptides have been used for the treatment of AD but they were ineffective because of their limited biological half-life. We have recently developed a highly efficient mouse dominant negative interleukin (IL)-4/IL-13 antagonist (IL-4DM), which blocks both IL-4 and IL-13 signal transductions. OBJECTIVE: To examine the effects of IL-4DM in vivo in an AD model induced by the repeated exhibition of oxazolone (OX). METHODS: Plasmid DNA was injected intraperitoneally to cause an experimental AD-like dermatitis. The effect was evaluated by ear thickness, histological findings, and mast cells counts in the inflamed skin. The plasma IgE and histamine levels were measured. Cytokine production in skin and splenocytes were also analysed. RESULTS: Mice treated with control plasmid developed marked dermatitis with mast cells and eosinophil infiltration, and had increased plasma IgE and histamine levels with a Th2 type splenocyte cytokine profile. Treatment with mouse IL-4 DNA augmented the ear swelling and thickness with an increased dermal eosinophil count, plasma histamine level, and production of splenocyte IL-4. However, IL-4DM treatment successfully controlled the dermatitis, decreased the mast cell and eosinophil count, and suppressed plasma IgE and histamine levels. Splenocytes produced an increased level of IFN-gamma. CONCLUSION: These data showed that the simultaneous suppression of IL-4/IL-13 signals successfully controlled Th2-type chronic dermatitis. IL-4DM DNA treatment is a potent therapy for AD and related diseases.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Dermatitis, Atopic/drug therapy , Interleukin-13/antagonists & inhibitors , Interleukin-4/antagonists & inhibitors , Th2 Cells/immunology , Vaccines, DNA/therapeutic use , Animals , Dermatitis, Atopic/immunology , Disease Models, Animal , Drug Evaluation, Preclinical , Interleukin-13/immunology , Interleukin-4/immunology , Male , Mice , Mice, Inbred BALB C , Statistics as TopicABSTRACT
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by elevated serum levels of IgE. AD is associated with Th2 cytokines including interleukin (IL)-4, IL-5, IL-13 and IL-10. Systemic administration of suplatast tosilate (IPD) is currently used to treat Th2 cytokine-mediated AD. OBJECTIVES: To evaluate the effect of topical IPD on skin lesions of AD using a genetically engineered AD mouse model (K14/caspase-1 transgenic mouse: KCASP1Tg). METHODS: IPD ointment (3%) and white petrolatum (WP) were applied to KCASP1Tg mice every other day from 6 to 14 weeks after birth. Histopathological analysis of skin lesions and measurement of mRNA expression of cytokines in skin lesions and spleen cells were carried out. We also compared changes in serum parameters between IPD-treated and WP-treated KCASP1Tg mice. RESULTS: WP-treated mice developed dermatitis at 8 weeks after birth. However, skin lesions in IPD-treated mice were limited. Histopathologically, skin lesions in WP-treated KCASP1Tg mice showed marked inflammatory changes with increased mast cell infiltration. However, mice treated with IPD showed minimum skin lesions with scarce mast cell infiltration. WP-treated KCASP1Tg mice had significant elevation in the serum levels of histamine, IgE and IL-18 as compared with IPD-treated KCASP1Tg mice. mRNA expression of IL-4 and IL-5 in the skin lesions from WP-treated KCASP1Tg mice was significantly higher than in those from IPD-treated mice. In the spleen, the expression of IL-4, IL-5 and interferon-gamma was significantly increased in WP-treated KCASP1Tg mice as compared with their IPD-treated counterparts. CONCLUSIONS: This study shows that topical therapy with IPD inhibits the expression of IL-4 and IL-5 and ameliorates skin manifestations in an AD mouse model, suggesting the potential usefulness of topical IPD for the treatment of AD.
Subject(s)
Anti-Allergic Agents/administration & dosage , Arylsulfonates/administration & dosage , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Interleukin-4/immunology , Interleukin-5/immunology , Sulfonium Compounds/administration & dosage , Administration, Topical , Animals , Anti-Allergic Agents/therapeutic use , Arylsulfonates/therapeutic use , Caspase 1/genetics , Dermatitis, Atopic/pathology , Down-Regulation , Histamine/blood , Immunoglobulin E/blood , Interferon-gamma/immunology , Interleukin-4/genetics , Interleukin-5/genetics , Male , Mast Cells/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , RNA, Messenger/analysis , Skin/immunology , Skin/pathology , Spleen/immunology , Sulfonium Compounds/therapeutic use , Th2 Cells/immunologyABSTRACT
A 42-year-old woman developed severe erythema with exfoliative scaling on the bilateral palms and soles and erosive dermatitis on the axillae and groin eight days after an autologous peripheral blood stem cell transplantation for the treatment of non-Hodgkin's lymphoma. She also developed exanthema; however she did not show intestinal, hepatic, or renal involvement. The skin biopsy revealed characteristic apoptotic cell death of the epidermis with eosinophilic necrosis, and she was diagnosed with acute graft-versus-host disease (GVHD). The cutaneous lesions responded to topical corticosteroid treatments and improved within a month without systemic immunosuppressing therapies. The cutaneous GVH reaction did not recur. However, she was treated with an intermittent thrombocyte transfusion because of persistent thrombocytopenia. On day 130, she developed intestinal pneumonia and died due to respiratory dysfunction. Unlike an allo-bone marrow graft, GVHD after an autologous stem cell transplantation is not common. Even for an autologous transplantation, GVH may develop with less characteristic clinical manifestations.
