Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase

Previously, we observed in a rat model that intravenous administration of i ntramuscular immunoglobulin preparations induced a long-lasting hypotension , which appeared to be associated with the presence of IgG polymers and dim ers in the preparations, but unrelated to complement activation. We found e vidence that this hypotensive response is mediated by platelet-activating f actor (PAF) produced by macrophages. In this study, we compared the vasoact ive effects of 16 intravenous immunoglobulin (IVIG) products from 10 differ ent manufacturers, in anesthetized rats, Eight of the IVIG preparations sho wed no hypotensive effects (less than 15% decrease), whereas the other 8 ha d relatively strong effects (15%-50% decrease). The hypotensive effects cor related with the IgG dimer content of the preparations. Pretreatment of the rats with recombinant PAF acetylhydrolase completely prevented the hypoten sive reaction on IVIG infusion, and administration after the onset of hypot ension resulted in normalization of the blood pressure. We also observed PA F production on in vitro incubation of human neutrophils with IVIG, which c ould be blocked by anti-Fc gamma receptor antibodies. This indicates that i nduction of PAF generation may also occur in a human system. Our findings s upport the hypothesis that the clinical side effects of IVIG in patients ma y be caused by macrophage and neutrophil activation through interaction of IgG dimers with Fc gamma receptors, Because phagocyte activation may also l ead to the release of other inflammatory mediators, recombinant PAF acetylh ydrolase (rPAF-AH) provides a useful tool to determine whether PAF plays a role in the clinical side effects of IVIG. If so, rPAF-AH can be used for t he treatment of those adverse reactions. (C) 2000 by The American Society o f Hematology.