The intraperitoneal administration of CAWS (water-soluble extracellular polysaccharide fraction obtained from the culture supernatant of Candida albicans) to mice induces coronaritis similar to Kawasaki disease. We analyzed differences in the production of cytokines involved in the occurrence of coronary arteritis among mouse strains, C3H/HeN, C57BL/6, DBA/2 and CBA/J that were injected with CAWS at 4 mg/mouse for 5 consecutive days in the first week and the fifth week of administration. The incidence of arteritis was 100% in C57BL/6, C3H/HeN and DBA/2 mice, but only 10% in CBA/J mice. The coronary arteritis observed in DBA/2 mice was the most serious, with several mice expiring during the observation period. The CAWS-sensitive strains revealed increased levels of IL-6 and IFN-gamma during the course of a specific response to CAWS by spleen cells. In contrast, IL-10 levels were observed to increase markedly in CAWS-resistant CBA/J mice, but not the CAWS-sensitive strains. However, TNF-alpha levels were more elevated only in DBA/2 mice. The difference in disease development and cytokine production strongly suggests that the genetic background of the immune response to CAWS contributes to the occurrence of coronary arteritis.
Coronary arteritis, a complication of Kawasaki disease (KD), can be refractory to immunoglobulin (IVIG) treatment. To determine the most effective alternative therapy, we compared the efficacy of different agents in a mouse model of KD. Vasculitis was induced by injection of Candida albicans water-soluble fractions (CAWS) into a DBA/2 mouse, followed by administration of IVIG, etanercept, methylprednisolone (MP), and cyclosporine-A (CsA). At 2 and 4 weeks, the mice were sacrificed, and plasma cytokines and chemokines were measured. CAWS injection induced active inflammation in the aortic root and coronary arteries. At 2 weeks, the vasculitis was reduced only by etanercept, and this effect persisted for the subsequent 2 weeks. At 4 weeks, IVIG and CsA also attenuated the inflammation, but the effect of etanercept was more significant. MP exerted no apparent effect at 2 or 4 weeks. The suppressive effect exerted by etanercept on cytokines, such as interleukin- (IL-)6, IL-12, IL-13, and tumor necrosis factor-α (TNF-α), was more evident than that of others. The extent of arteritis correlated with the plasma TNF-α levels, suggesting a pivotal role of TNF-α in KD. In conclusion, etanercept was most effective in suppressing CAWS-induced vasculitis and can be a new therapeutic intervention for KD.
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