Siragam V, Crow AR, Brinc D, et al. Intravenous immunoglobulin ameliorates ITP via activating Fcgamma receptors on dendritic cells. Nat Med 2006;12:688-692.IVIg has been used across a spectrum of autoimmune disease with success in idiopathic thrombocytopenic purpura (ITP) but has been of limited use in other diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. In this manuscript, the authors probe the mechanism of IVIg’s efficacy in ITP and hypothesize, based upon their findings presented here and those in an earlier manuscript, a model to refine therapy in ITP and explain why IVIg may not work in those diseases where there is evidence of significant circulating immune complexes. Here, the investigators use a mouse model and generate ITP by the injection of an antibody to platelets and take advantage of mouse strains where components thought to be important in modulating ITP have been deleted. Previous work by others demonstrated that the inhibitory Fcγ receptor, FcγRIIB is critical to the action of ITP and that increased expression of this receptor on macrophages is associated with reduced platelet clearance. In this work, the investigators demonstrate that cells of the innate immune system, but not lymphocytes, are central for mediating the effect of IVIg on ITP. Expression of FcγRIIB in the recipient is important for treating ITP but its expression is not necessary on the leukocytes. Activating signals from other Fc receptor family members are shown to be involved in IVIg action and an antibody that directly activates FcγIIIA on leukocytes treats ITP. Crosslinking of this receptor diminishes ITP even in those mice where FcRγIIB is not expressed. Furthermore, direct activation of the Fcγ chain ameliorated ITP. Selection of splenic leukocytes with antibodies established that only CD11c + dendritic cells ameliorated ITP and other leukocytes or isolated macrophages did not.
The overall model established from this manuscript is that IVIg works by interacting with Fcγ receptors on dendritic cells and, more specifically, with the activating FcRIIIA. The work points to a functional role for the inhibitory receptor in their mouse model, but this may occur as a downstream event in IVIg action. Of note is that IVIg does not work in diseases where there is a high level of circulating immune complexes such as SLE. One hypothesis to explain this is that high levels of circulating antibodies may result in down modulation of either expression or activating signals of the Fcγ receptors and there is little benefit to giving IVIg in these cases. Although this is a plausible explanation, direct proof of this has yet to be obtained.
The work presented here focuses on a mouse model of ITP; nonetheless, the findings are of interest because not only do they suggest a model whereby IVIg works, but they also shed light on our understanding of why this therapy gives such variable effects in immune-mediated processes. Furthermore, the work sets forth potential areas to develop more refined therapeutic agents. It may be feasible to directly activate FcRIIIA by a specific antibody. Although direct activation of dendritic cells holds appeal, the isolation, treatment, and reinfusion may be less attractive than targeting the FcγIIIA receptor. The next step will involve applying these findings to human diseases, assessing whether treatment of human leukocytes with FCRIIIA antibodies results in activation of signals or whether the gamma chain needs to be directly targeted. Moving away from the complex issues associated with IVIg to a more specific and targeted therapy is an attractive goal.
