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The first publication on intravenous immunoglobulin (IVIG) administration for children with immune thrombocytopenia ITP (Imbach et al.,The Lancet 1981; 1:1228-1231) evoked targeted immunomodulation in patients with inflammatory and autoimmune disorders.We update the development of the immunomodulatory effects of IVIG over the last 28 years.The key patient in 1980 was a boy with severe ITP and secondary hypogammaglobulinemia due to long-term immunosuppressive treatment.Following administration of IVIG the boy s platelet counts started to increase and in a subsequent pilot study of 12 consecutive children with ITP,but without hypogammaglobulinemia,the same phenomenon was observed.Since then,there have been controlled clinical trials of IVIG in patients with ITP as well as in other inflammatory or autoimmune disorders.Examples of documented immunomodulation are today:in hematology:graft versus host disease,,allograft recipients,autoimmune lypmphoproliferative syndrome and others,in neurology:Guillain-Barré syndrome,,myasthenia gravis,multifocal motor neuropathy,remitting-relapsing multiple sclerosis and others,in dermatology:autoimmune mucocutaneous blistering diseases,pemphigus,Stevens-Johnson syndrome and others.Extensive studies on the mechanisms of action of IVIG have documented the immunomodulatory interaction in the disturbed immune response in these patients.Today,the clinical efficacy and marketing success ofIVIG has resulted in high demand for the product,although the mechanisms of action of IVIG remain far from being clear.Nonetheless,the worldwide annual use of IVIG increased remarkably,from 300 kg to 70,000 kg over the last 28 years.IVIG is extracted from the pooled plasma of 10,000-100,000 blood or plasma donations.The safety of IVIG is controlled by ongoing careful selection and deferral of donors,by testing and validation of donated blood and plasma as well as during the steps of production including the purification processes.Thus,the human derived product IVIG challenged therapeutic approaches from immunosuppression to biologic immunomodulation in many inflammatory and autoimmune disorders.