Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1856-1861
Vasoactive side effects of intravenous immunoglobulin preparations
in a rat model and their treatment with recombinant platelet-activating
factor acetylhydrolase
Wim K. Bleeker,
Jessica L. Teeling,
Arthur J. Verhoeven,
Gemma M. M. Rigter,
Jacques Agterberg,
Anton T. J. Tool,
Anky H. L. Koenderman,
Taco W. Kuijpers, and
C. Erik Hack
From CLB, Amsterdam, The Netherlands.
Previously, we observed in a rat model that intravenous
administration of intramuscular immunoglobulin preparations induced a
long-lasting hypotension, which appeared to be associated with the
presence of IgG polymers and dimers in the preparations, but unrelated
to complement activation. We found evidence that this hypotensive
response is mediated by platelet-activating factor (PAF) produced by
macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different
manufacturers, in anesthetized rats. Eight of the IVIG preparations
showed no hypotensive effects (less than 15% decrease), whereas the
other 8 had relatively strong effects (15%-50% decrease). The
hypotensive effects correlated with the IgG dimer content of the
preparations. Pretreatment of the rats with recombinant PAF
acetylhydrolase completely prevented the hypotensive reaction on IVIG
infusion, and administration after the onset of hypotension resulted in
normalization of the blood pressure. We also observed PAF production on
in vitro incubation of human neutrophils with IVIG, which could be
blocked by anti-Fc
receptor antibodies. This indicates that
induction of PAF generation may also occur in a human system. Our
findings support the hypothesis that the clinical side effects of IVIG
in patients may be caused by macrophage and neutrophil activation
through interaction of IgG dimers with Fc receptors. Because
phagocyte activation may also lead to the release of other inflammatory
mediators, recombinant PAF acetylhydrolase (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 the treatment of
those adverse reactions.
