Intravenous Immunoglobulins (IVIg) infusion is an approved therapy for immunodeficiency and is prescribed for autoimmune and systemic inflammatory diseases because of its anti-inflammatory activity. However, the molecular basis for its anti-inflammatory activity is controversial and cannot be extrapolated from studies on animal models of disease.

We have demonstrated that IVIg modifies the macrophage transcriptional and functional polarization in a cell type-dependent manner, and that the IVIg´s ability to impair tumor growth and metastasis in animal models of disease correlates with its ability to shape macrophage polarization. We have also determined that, in vivo, IVIg provokes a rapid increase in activin A, CCL2 and IL-6 levels in peripheral blood, and that, in vitro, IVIg impairs the M-CSF-dependent generation of anti-inflammatory macrophages through enhancement of JNK activation and activin A production, and limits the pro-inflammatory differentiation of monocytes by inhibiting GM-CSF-driven STAT5 activation. Importantly, IVIg has been found to alter the transcriptional and cytokine profile of human macrophages, and to promote an increase in the expression of negative regulators of TLR-initiated intracellular signaling, including A20, SHIP1 and SHP1. Our current hypothesis is that IVIg conditions human macrophages towards the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that would explain the net anti-inflammatory action of IVIg in vivo.

Strategies to determine the basis for the anti-inflammatory action of IVIg