A novel mechanism for intravenous immunoglobulin therapy

Despite increasing usage of intravenous immunoglobulin (IVIg) therapy in a laundry list of clinical conditions, the mechanism for its activity is still incompletely defined. IVIg is a preparation of purified antibodies pooled from the plasma of thousands of donors. It emerged in the 1950's as a treatment for individuals with antibody deficiencies. In 1981, Paul Imbach and colleagues identified therapeutic activity of IVIg in autoimmune disease. This seminal finding triggered the expansion of IVIg therapy to a growing number of diseases. Many studies have contributed to our understanding of the mechanisms of action of IVIg. However, the precise mode of action remains somewhat enigmatic due to contrasting anti-inflammatory and pro-inflammatory activities of IVIg depending on the disease context. In an article recently published in the Journal of Immunology, Dr. Angeles Dominguez-Soto, Dr. Angel L. Corbi and their colleagues describe a new mechanism which at least partially explains these contradictions. Their data suggests a model where IVIg activates monocytes and macrophages through receptors common on such cells, known as Fc-gamma receptors. Fc-gamma receptors specifically bind the conserved stem of the immunoglobulins. The binding of these receptors to the antibodies 'turns on' the cells, resulting in increased cytokine levels in both human blood and in cell culture. However, because the cells are already 'on', they are not as sensitive to additional signals that they might encounter as they move into inflamed tissue. In fact, the data show that macrophages which develop from monocytes in the presence of IVIg have diminished ability to develop either an inflammatory or anti-inflammatory gene program. In summary, IVIg therapy appears to work, at least in part, by neutering the macrophages before they enter tissues through premature excitation. As an additional point of interest for obstetrics, one of the cytokines induced by IVIg is activin A, which has activities protective for the oocyte and pregnancy. It appears certain that numerous mechanisms contribute to the outcomes of IVIg therapy. However, the data from Dominguez-Soto and colleagues sheds light on the contradictary inflammatory and anti-inflammatory properties of IVIg.

References:

Dominguez-Soto, A. et al. 2018. IVIg Promote Cross-Tolerance against Inflammatory Simuli In Vitro and In Vivo. The Journal of Immunology. 201:41-52.

Branch. D.R. 2013. Unraveling the IVIg mystique. Transfusion. 53:242-244.

Jolles, S., W.A.C. Sewell & S.A. Misbah. Clinical uses of intravenous immunoglobulin. Clinical & Experimental Immunology. 2005: 1-11.

Grand View Research. 2018. Intravenous Immunoglobulin (IVIG) Market Size, Share & Trend Analysis Report By Application (Hypogammaglobulinemia, CIDP, Congenital AIDS), By Route of Administration, And Segment Forecasts, 2012 - 2022. Webpage accessed 8/2/2018. https://www.grandviewresearch.com/industry-analysis/intravenous-immunoglobulin-market.