Mizoribine provides effective treatment of sequential histological change of arteritis and reduction of inflammatory cytokines and chemokines in an animal model of Kawasaki disease

Kei Takahashi; Toshiaki Oharaseki; Tomokazu Nagao; Yuki Yokouchi; Hitomi Yamada; Noriko Nagi-Miura; Naohito Ohno; Tsutomu Saji; Tomio Okazaki; Kazuo Suzuki

doi:10.1186/1546-0096-9-30

Mizoribine provides effective treatment of sequential histological change of arteritis and reduction of inflammatory cytokines and chemokines in an animal model of Kawasaki disease

Pediatr Rheumatol Online J. 2011 Sep 29;9(1):30. doi: 10.1186/1546-0096-9-30.

Authors

Kei Takahashi¹, Toshiaki Oharaseki, Tomokazu Nagao, Yuki Yokouchi, Hitomi Yamada, Noriko Nagi-Miura, Naohito Ohno, Tsutomu Saji, Tomio Okazaki, Kazuo Suzuki

Affiliation

¹ Inflammation Program, Dept, of Immunology, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-8670, Japan. ksuzuki@faculty.chiba-u.jp.

Abstract

The incidence of panvasculitis in the coronary arteries and aortic root was 100% in the control group. The incidence of panvasculitis in the MZR group decreased to 50%. Moreover, the scope and severity of the inflammation of those sites were significantly reduced in the MZR group as well as the IgG group. On the other hand, increased cytokines and chemokines, such as IL-1α, TNF-α, KC, MIP-1α, GM-CSF, and IL-13, in the nontreatment group were significantly suppressed by treatment with MZR, but the MCP-1 level increased. In addition, IL-1α, TNF-α, IL-10, IL-13, and MIP-1α were suppressed by treatment in the IgG group.

Background: Intravenous immunoglobulin (IVIg) treatment results in an effective response from patients with acute-phase Kawasaki disease (KD), but 16.5% of them remain nonresponsive to IVIg. To address this therapeutic challenge, we tried a new therapeutic drug, mizoribine (MZR), in a mouse model of KD, which we have established using injections of Candida albicans water-soluble fractions (CAWS).

Methods: CAWS (4 mg/mouse) were injected intraperitoneally into C57BL/6N mice for 5 consecutive days. MZR or IgG was administered for 5 days. After 4 weeks, the mice were sacrificed and autopsied, the hearts were fixed in 10% neutral formalin, and plasma was taken to measure cytokines and chemokines using the Bio-Plex system.

Results: The incidence of panvasculitis in the coronary arteries and aortic root was 100% in the control group. The incidence of panvasculitis in the MZR group decreased to 50%. Moreover, the scope and severity of the inflammation of those sites were significantly reduced in the MZR group as well as the IgG group. On the other hand, increased cytokines and chemokines, such as IL-1α TNF-α, KC, MIP-1α, GM-CSF, and IL-13, in the nontreatment group were significantly suppressed by treatment with MZR, but the MCP-1 level increased. In addition, IL-1α, TNF-α, IL-10, IL-13, and MIP-1α were suppressed by treatment in the IgG group.

Conclusion: MZR treatment suppressed not only the incidence, range, and degree of vasculitis, but also inflammatory cytokines and chemokines in the plasma of the KD vasculitis model mice, suggesting that MZR may be useful for treatment of KD.