The scope and efficacy of intravenous immunoglobulin therapy

Departing AAAAI president, Mark Ballow, MD, chose the mechanism(s) of action of IVIG (intravenous immunoglobulin) therapy as his contribution to this month’s presidential theme issue (J Allergy Clin Immunol 2011;127:315-323). Dr. Ballow reviews the interesting research that has begun to characterize how IGIV modulates the immune and inflammatory pathways that are associated with a variety of diseases.

Dr. Ballow begins by noting that anaphylaxis risks dictated that early IG therapy for humoral and B-cell immune deficiencies be given by intramuscular route, but by the 1980’s an intravenous preparation was available, making the therapy even more effective in establishing normal serum IgG levels in immunodeficiency patients. Serendipitous observation was made that IVIG therapy also increased platelet counts significantly in patients with co-morbid idiopathic thrombocytopenia purpura (ITP) and led to research on IVIG therapy for other autoimmune/inflammatory diseases. Dr. Ballow points out that approximately 70% of IVIG therapy administered currently is used to treat autoimmune and inflammatory disorders.

The review discusses the multiple mechanisms that have been described for IgG therapy in the context of the diseases in which they have been identified. For example, Fc receptor blockade effects by IVIG were first described in patients with ITP. Other authors reported that idiotypic antibodies in the IVIG neutralizes the autoantibodies that lead to acquired hemophilia, though Fc receptor interactions were found more commonly in other disorders. Research on IVIG efficacy for Kawasaki disease, dermatomyositis, and toxic epidermal necrolysis revealed that IgG therapy had the capacity to interfere in many places along and within the inflammatory cascade at the cellular levels and with inflammatory mediators, such as cytokine inhibition, chemokine production, suppression of adhesion molecule activity, inhibition of complement binding, and modulation of apoptotic processes through anti-Fas antibody components.

Dr. Ballow also describes other research on IVIG immune-modulating mechanisms associated with the Fc inhibitory receptor, FcRIIB, and C-type lectin receptors on effector macrophages that may act to reduce circulating autoantibodies. Finally, the author discusses recent findings that IgG increased suppressive function of Tregs and that therapy in Kawasaki disease and Guillain-Barré syndrome is associated with increased numbers of T regulatory cells.

Dr. Ballow wraps up commenting that “the IgG molecule is the single most important naturally occurring specific immune component capable of modulating the immune system.” Further, that many mechanisms for IVIG efficacy have been identified and that it is likely that they all work in concert depending on IVIG dose and disease context.

We asked Dr. Ballow to tell us about why we chose this focus for his presidential theme issue:

Dr. Ballow: This is the 100th year anniversary for "traditional" immunotherapy celebrated in the Jan. issue of JACI. However, allergist/immunologist have to go beyond traditional immunotherapy (IT) to other forms of "immune therapy" including bone marrow transplantation for patients with primary immune deficiency, IVIG as replacement therapy in patients with hypogammaglobulinemia, and immune response modifiers such as monoclonal antibodies, fusion proteins. The latter therapies have carved an important treatment modality in patients with autoimmune diseases (see review by Betty Diamond). In fact, IVIG has turned out to be one of the most important immune response modifiers in the treatment of inflammatory and autoimmune disease. These topics are emphasized in the upcoming annual Academy meeting, and underscores one of my Presidential themes of expanding the scope of practice for the allergist/immunologist. My motto - "better health through immune based therapies."