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

Abstract

Behcet'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.