The role of CCR1 and therapeutic effects of anti‐CCL3 antibody in herpes simplex virus‐induced Behçet's disease mouse model

• Published in: Immunology Vol. 158; no. 3; pp. 206 - 218
• Main Authors: Sayeed, Hasan M., Lee, Eun‐So, Byun, Hae‐Ok, Sohn, Seonghyang
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.11.2019; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Antibodies; Antibodies - pharmacology; Behcet Syndrome - drug therapy; Behcet Syndrome - immunology; Behcet Syndrome - pathology; Behcet Syndrome - virology; Behcet's syndrome; Behçet's disease; CC chemokine receptors; CCL3; CCL3 protein; CCR1; CCR1 protein; Chemokine CCL3 - antagonists & inhibitors; Chemokine CCL3 - immunology; Chemokines; Colchicine; Control; Cytoplasm; Disease Models, Animal; Flow cytometry; Herpes simplex; Herpes Simplex - drug therapy; Herpes Simplex - immunology; Herpes Simplex - pathology; herpes simplex virus; Herpes viruses; Humans; inflammation; Inflammatory diseases; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - pathology; Ligands; Lymph nodes; Male; Mice; Mice, Inbred ICR; mouse model; Original; Peripheral blood mononuclear cells; Plasma levels; Receptors, CCR1 - immunology; Signs and symptoms; Simplexvirus - immunology; Viruses; CCR1; herpes simplex virus; CCL3; Behçet's disease; mouse model; inflammation
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13102

Summary Behçet's disease (BD) is a chronic systemic inflammatory disease with unclear etiopathogenesis. Although gene variants of CC chemokine receptor type 1 (CCR1) have been reported, the protein expression of CCR1 in patients with BD remains unclear. The objective of this study was to analyze the frequencies of CCR1+ cells in a herpes simplex virus‐induced mouse model of BD. The frequencies of CCR1+ cells on the surface and in the cytoplasm of peripheral blood mononuclear cells and lymph nodes were analyzed by flow cytometry. The CCR1+ cells were significantly down‐regulated in BD mice compared with the normal control and symptom‐free control mice. Colchicine and pentoxifylline treatment improved the symptoms of BD and increased the frequencies of CCR1+ cells in BD mice. Treatment with chemokine CC motif ligand 3 (CCL3), a ligand of CCR1, caused BD symptoms to deteriorate in 10 of 16 BD mice (62·5%) via down‐regulation of CCR1+ cells. Anti‐CCL3 antibody treatment ameliorated BD symptoms in 10 of 20 mice (50%) and significantly decreased the disease severity score compared with CCL3‐treated BD mice (P = 0·01) via up‐regulation of CCR1+ cell frequencies. In patients with BD, plasma levels of CCL3 in an active state were significantly higher than in healthy control individuals (P = 0·02). These results show that the up‐regulation of CCR1+ cells was related to the control of systemic inflammation of BD in mouse models. The frequencies of CCR1 positive cells were down‐regulated in peripheral blood leukocytes of Behçet's disease symptomatic mice. CCL3, a ligand of CCR1, induced down‐regulation of CCR1 positive cells. The treatment of anti‐CCL3 antibody up‐regulated CCR1 positive cells and had an improvement effect on inflammatory symptoms in Behçet's disease mice.