Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 942-951
Immunoglobulin M-Enriched Human Intravenous Immunoglobulin Prevents
Complement Activation In Vitro and In Vivo in a Rat Model of Acute
Inflammation
Robert Rieben,
Anja Roos,
Yvonne Muizert,
Caroline Tinguely,
Arnout F. Gerritsen, and
Mohamed R. Daha
From the Departments of Cardiology and Hematology, Bern University
Hospital, Bern, Switzerland; and the Department of Nephrology, Leiden
University Medical Center, Leiden, The Netherlands.
An important antiinflammatory mechanism of intravenous
immunoglobulin preparations (IVIG) is their ability to block complement activation. The purpose of this study was to compare the
complement-inhibitory activity of four IVIG preparations differing in
isotype composition. The preparations were: (1) IVIgG (48 g/L IgG, 2 g/L IgA; Intraglobin F); (2) Pentaglobin (38 g/L IgG, 6 g/L IgM, 6 g/L
IgA); (3) IVIgM (35 g/L IgM, 12 g/L IgA, 3 g/L IgG); and (4) IVIgA (41 g/L IgA, 9 g/L IgG), all from Biotest Pharma GmbH, Dreieich, Germany.
Their complement inhibitory activity was assessed in vitro by
measurement of the blocking of C1q-, C4-, and C3
deposition on solid-phase aggregated rabbit IgG by enzyme-linked
immunosorbent assay (ELISA). Complement inhibition in this ELISA was
best for IVIgM, followed by Pentaglobin and IVIgG; IVIgA did not
exhibit an inhibitory effect. Control experiments with excess
concentrations of C1q as well as with C1q-depleted serum showed that
the inhibitory effects of IVIG were not caused by complement activation
and thus, consumption, but that C4 and C3 were scavenged by IgM and to
a lesser extent by IgG. These results were confirmed in vivo in the rat
anti-Thy 1 nephritis model, in which a single dose of 500 mg/kg of
IVIgM prevented C3-, C6-, and C5b-9 deposition in the rat glomeruli,
whereas the effect of IVIgG was much less pronounced. Reduction of
complement deposition was paralleled by a diminished albuminuria, which
was completely absent in the IVIgM-treated rats. IVIgM and to a lesser
extent IVIgG also prevented rat C3 deposition on cultured rat
glomerular mesangial cells in vitro, but did not influence anti-Thy 1 binding. Neither IVIgM nor Pentaglobin nor IVIgG negatively affected in
vitro phagocytosis of Escherichia coli (E coli)
by human granulocytes. In conclusion, we have shown that IgM enrichment
of IVIG preparations enhances their effect to prevent the inflammatory
effects of complement activation.
