Abstract
BackgroundIntravenous 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).MethodsCAWS (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.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.ResultsThe 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.ConclusionMZR 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.
Highlights
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
Since the etiology and development of KD are thought to be due to the dysfunction of the immune system, intravenous immunoglobulin (IVIg) during the early acute phase has been used with an excellent response in most patients [3]
Histological evaluation of panvasculitis in treatment with MZR Panvasculitis developed in the coronary arteries and the aortic root, and histology was similar to that previously described [33]
Summary
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. Since the etiology and development of KD are thought to be due to the dysfunction of the immune system, intravenous immunoglobulin (IVIg) during the early acute phase has been used with an excellent response in most patients [3]. 16.5% of patients did not respond to the first IVIg treatment [4], and some nonresponders to the first IVIg treatment manifested severe coronary arteritis with large aneurysm [5]. For treatment of patients with KD who do not respond to IVIg, other medicines for immune response and suppression of lymphocyte proliferation have been applied due to immune dysfunction in the patients. Mizoribine (MZR), a drug that inhibits synthesis of purine compounds (GMP), blocks proliferation of lymphocytes and will be useful for application to nonresponders to IVIg treatment.
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