Gupta M, Noel G J, Schaefer M, Friedman D, Bussel J, Johann-Liang R
Department of Pediatrics, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, USA.
J Clin Immunol. 2001 May;21(3):193-9. doi: 10.1023/a:1011039216251.
Intravenous immune gamma-globulin (IVIG) is used successfully in the treatment 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 clearly understood. Recently anticytokine antibodies in IVIG have been demonstrated. Serum levels of proinflammatory cytokines have been shown to be elevated in patients with Kawasaki disease. The cytokine interleukin-6 (IL-6) is involved in the de novo production of acute-phase proteins by hepatocytes and cause thrombocytosis and fever in response to tissue injury. Patients receiving parenteral recombinant human IL-6 have dose-dependently experienced fever, malaise, chills, and acute-phase reaction. With high IL-6 concentrations, central nervous system toxicity has also been reported and IL-6 has 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-alpha (but not sIL-6R) in peripheral blood induced by stimulation with LPS were markedly reduced (P < 0.008) within 3 hr when incubated with IVIG compared to without IVIG. Thus we demonstrated that cells of normal children respond to IVIG in vitro by reducing cytokines such 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 higher IL-6 levels in children with Kawasaki disease compared to children with blood culture-negative febrile illnesses. In five children with Kawasaki disease we measured serum IL-6 before and after IVIG and assessed the clinical response to IVIG therapy. Therapy with IVIG was followed by a rapid resolution 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 resolution of symptoms and decrease in the acute-phase proteins in children with Kawasaki disease. Cells of normal children were found to respond to the IVIG in a manner similar to that of the Kawasaki children.
静脉注射免疫球蛋白（IVIG）已成功用于川崎病的治疗，可使发热、烦躁等症状迅速消退，且呈剂量依赖性，同时血沉、白细胞和血小板数量也会下降。IVIG减轻这种炎症反应的作用机制尚不清楚。最近已证实IVIG中存在抗细胞因子抗体。川崎病患者的促炎细胞因子血清水平已被证明有所升高。细胞因子白细胞介素-6（IL-6）参与肝细胞从头合成急性期蛋白，并在组织损伤时引起血小板增多和发热。接受肠胃外重组人IL-6治疗的患者会出现剂量依赖性的发热、不适、寒战和急性期反应。在IL-6浓度较高时，也有中枢神经系统毒性的报道，并且认为IL-6可介导内皮损伤。我们评估了12名正常儿童受刺激的血细胞对IVIG在细胞因子IL-6、IL-8、肿瘤坏死因子-α（TNF-α）和IL-6受体（sIL-6R）释放方面的反应。与未使用IVIG相比，在与IVIG孵育3小时内，脂多糖刺激诱导的外周血中细胞因子IL-6、IL-8和TNF-α（但不包括sIL-6R）水平显著降低（P < 0.008）。因此，我们证明正常儿童的细胞在体外对IVIG的反应是通过减少IL-8、TNF-α和IL-6等细胞因子，而在急性炎症反应期间不影响受体sIL-6R的水平。我们还发现，与血培养阴性的发热性疾病儿童相比，川崎病儿童的IL-6水平明显更高。在5名川崎病儿童中，我们测量了IVIG治疗前后的血清IL-6，并评估了对IVIG治疗的临床反应。IVIG治疗后，川崎病的症状迅速消退，血清IL-6显著下降。输注IVIG后促炎细胞因子反应的减弱，尤其是IL-6的减弱，可能在川崎病儿童症状的迅速消退和急性期蛋白的减少中起重要作用。发现正常儿童的细胞对IVIG的反应方式与川崎病儿童相似。
