The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease

Abstract

The introduction of intravenous immunoglobulin (IVIG) for modulation of inflammation in acute Kawasaki disease was a great therapeutic triumph. However, three decades later, the mechanisms underlying immune regulation by IVIG are only beginning to be revealed. Stimulation of an immature myeloid population of dendritic cells that secretes IL-10 and the elucidation of Fc-specific natural regulatory T cells provide insights into the mechanisms of IVIG. Other potential mechanisms include provision of agent-specific neutralizing antibody, anti-idiotype and anti-cytokine antibodies, blockade of activating Fcγ receptors and stimulation of the inhibitory FcγRIIb receptor. New initiatives must seek to understand the mechanisms of IVIG in order to replace it one day with more affordable and more targeted therapies.

Keywords:

• acquired heart disease
• coronary artery aneurysms
• immune regulation
• Kawasaki disease
• myocardial infarction
• pediatric vasculitis

Financial & competing interests disclosure

The authors were supported by grants from the National Institutes of Health (grant numbers: NIH R01 HL103536 to A Franco and JC Burns and U54 HL108460 to JC Burns) and from the University of California (UCSD – UL1 RR031980 to A Franco). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Intravenous immunoglobulin (IVIG) likely acts through many different pathways in Kawasaki disease (KD) to achieve the down-regulation of systemic and tissue-level inflammation, but little is known about the underlying mechanisms.

• Mechanisms involving the Fab′ region may include neutralization of the inciting agent, toxin or superantigen and neutralization of pro-inflammatory molecules including cytokines, but there is no specific experimental data that addresses these possibilities.

• T cell regulation appears to be important at the tissue level for the resolution of inflammation in Kawasaki disease and evidence suggests that the Fc stimulates immature myeloid dendritic cells to secrete IL-10 and leads to the expansion of regulatory T cells and that Fc peptides are processed and presented by APCs to a specialized subset of Fc-specific natural regulatory T cells that proliferate and secrete IL-10. It is proposed that these mechanisms modulate vascular inflammation as Fc-specific natural regulatory T cells from patients who develop aneurysms fail to expand in vitro when incubated with purified Fc fragments but do expand when incubated with recombinant peptides from specific regions of the Fc.

• Preliminary data suggest that enzymes involved in sialylation of native IgG molecules may play a role in IVIG resistance.

• Polymorphisms associated with IVIG resistance have been described, but await validation. These findings suggest that IVIG resistance may be influenced by host genetics.

Notes