Cytokine modulation with immune gamma-globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment

Intravenous immune gamma -globulin (IVIG) is used successfully in the treat ment of Kawasaki disease, with dose-dependent rapid resolution of symptoms such as fever and irritability and a decrease in ESR, WBCs, and platelets. The mode of action of IVIG in reducing this inflammatory response is not cl early understood. Recently anticytokine antibodies in IVIG have been demons trated. Serum levels of proinflammatory cytokines have been shown to be ele vated in patients with Kawasaki disease. The cytokine interleukin-6 (IL-6) is involved in the de novo production of acute-phase proteins by hepatocyte s and cause thrombocytosis and fever in response to tissue injury. Patients receiving parenteral recombinant human IL-6 have dose-dependently experien ced fever, malaise, chills, and acute-phase reaction. With high IL-6 concen trations, central nervous system toxicity has also been reported and IL-6 h as been thought to mediate endothelial damage. We evaluated the response of stimulated blood cells of 12 normal children to IVIG in the release of the cytokines IL-6, IL-8, TNF-alpha, and IL-6 receptor (sIL-6R). The levels of cytokines IL-6, IL-8, and TNF-ol (but not sIL-6R) in peripheral blood indu ced by stimulation with LPS were markedly reduced (P < 0.008) within 3 hr w hen incubated with IVIG compared to without IVIG. Thus we demonstrated that cells of normal children respond to IVIG in vitro by reducing cytokines su ch as IL-8, TNF-alpha, and IL-6 without affecting the level of receptor sIL -6R during an acute inflammatory response. We also found significantly high er IL-6 levels in children with Kawasaki disease compared to children with blood culture-negative febrile illnesses. In five children with Kawasaki di sease we measured serum IL-6 before and after IVIG and assessed the clinica l response to IVIG therapy. Therapy with IVIG was followed by a rapid resol ution of symptoms in Kawasaki disease, with a significant decrease in serum IL-6. The attenuation of proinflammatory cytokine responses, especially IL -6, following infusions of IVIG may play an integral role in the rapid reso lution of symptoms and decrease in the acute-phase proteins in children wit h Kawasaki disease. Cells of normal children were found to respond to the I VIG in a manner similar to that of the Kawasaki children.