Intravenous immunoglobulin and salicylate differentially modulate pathogenic processes leading to vascular damage in a model of Kawasaki disease

Abstract

Objective. Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development.Methods. Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor ␣ (TNF␣) production, and realtime polymerase chain reaction to examine TNF␣-mediated expression of matrix metalloproteinase 9 (MMP-9).Results. At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNF␣ expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNF␣ production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNF␣. TNF␣ activity was a prerequisite for local expression of MMP-9 at the coronary artery.Conclusion. Therapeutic concentrations of IVIG and salicylate differentially modulate the expression of TNF␣ and its downstream effects. Further dissection of the biologic effects of aspirin in acute KD is necessary for the rational design of therapy.

Intravenous Immunoglobulin Therapy in Primary Vasculitides

“…Gupta et al (2001) found reduction of proinflammatory cytokines Il-6, Il-8 and TNF-alfa in patients with KD. Lau et al (2009) confirmed in murine model of KD that IVIG in therapeutic concentrations, but not salicylate, effectively reduced the immune response leading to TNF-alpha expression. Possible mechanism published Siedlar et al (2011) when in vitro exposure of the healthy individuals' monocytes to the IVIG preparation resulted in reduced TNF production, which was overcome by blockade of the FcγRIIB in the CD14(+) CD16(++) CD32B(high) monocytes.…”

Of Mice and Children

“…6,7 The coronary arteritis is responsive to treatment with intravenous immunoglobulin, the mainstay of therapy for children with KD. 8,9 This model has also been exploited to demonstrate the beneficial effects of monoclonal antibody blockade of tumor necrosis factor-␣, an approach that is currently under study in 2 clinical trials of pediatric patients with acute KD. 10 -12 Other therapies demonstrated to be beneficial in this mouse arteritis model include matrix metalloproteinase inhibition with doxycycline and atorvastatin.…”

Plasma H2S predicts coronary artery lesions in children with Kawasaki disease

“…[13][14][15] KD is commonly considered a systemic vasculitis, which is characterized by inflammation and necrosis of blood vessels. 16,17 It has been reported that the plasma H 2 S level of KD patients is reduced, 18 but it is still unclear whether plasma H 2 S is a potentially useful biomarker for the prediction of CAL in children with KD.…”