Complement activation in cancer patients undergoing immunotherapy with
interleukin-2 (IL-2): binding of complement and C-reactive protein by
IL-2-activated lymphocytes
G Vachino, JA Gelfand, MB Atkins, JD Tamerius, P Demchak and JW Mier
Department of Medicine, Tufts University School of Medicine, Boston, MA.
Plasma samples from cancer patients undergoing immunotherapy with high-
dose recombinant interleukin-2 (IL-2) were obtained over a 5-day course of
treatment and assayed by radioimmunoassay or enzyme-linked immunosorbent
assay for the complement degradation products, C3a, iC3b, Ba, Bb, C4d, and
SC5b-9. In the majority of patients, pretreatment C3a, Ba, Bb, and SC5b-9
plasma levels were comparable with those measured in normal donor plasma.
However, by the end of the 5-day treatment course, C3a levels had increased
15.6-fold. In several patients, peak concentrations of C3a were as high as
those reported in patients with sepsis or burn injury. Plasma levels of
alternative pathway components Ba and Bb also increased, 8.0- and 5.0-fold,
respectively, during IL-2 treatment. Likewise, levels of one of the
terminal complexes, SC5b-9, increased 5.0-fold and the plasma C4d and iC3b
concentrations increased 4.8- and 2.9-fold, respectively, by the fifth day
of treatment. To determine whether activated lymphocytes participate in
IL-2-induced complement activation, peripheral blood mononuclear cells
(PBMC) obtained from IL-2 recipients before and 5 days after beginning
therapy were reacted with monoclonal antibodies (MoAbs) against C3c and the
terminal complement complex SC5b-9. Dual-color cytofluorographic analysis
showed that within the CD3(+) population, the percentage of cells binding
the anti-C3c and anti-SC5b-9 MoAbs increased 6.2-fold and 5.1-fold,
respectively, by day 5. The anti-C3c MoAb also bound to CD3(+) cells
stimulated in vitro with IL-2 and then exposed to serum. Moreover,
fluid-phase iC3b was generated from purified C3 by PBMC activated in vitro
with IL-2, but not by unstimulated cells. Serum levels of C-reactive
protein (CRP) are markedly elevated in patients undergoing IL-2
immunotherapy. This hepatic acute phase reactant has been shown to activate
the classical pathway when bound to cell surfaces. Because levels of the
classical component C4d increase markedly during IL-2 treatment, we sought
to determine if CRP became bound to PBMC during IL-2 treatment and found
that during therapy, the percentage of CD3(+) cells reactive with an
anti-CRP MoAb increased from less than 2% to greater than 18%. When PBMC
were activated with IL- 2 in vitro and then exposed to exogenous CRP,
greater than 20% of the CD3(+) cells reacted with the anti-CRP
MoAb.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 78,
Issue 10,
pp. 2505-2513,
11/15/1991
Copyright © 1991 by The American Society of Hematology
