1. Reduction of complement factor H binding to CLL cells improves the induction of rituximab-mediated complement-dependent cytotoxicity.
- Author
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Hörl, S, Bánki, Z, Huber, G, Ejaz, A, Windisch, D, Muellauer, B, Willenbacher, E, Steurer, M, and Stoiber, H
- Subjects
ENZYME activation ,CANCER cells ,RITUXIMAB ,CELL-mediated cytotoxicity ,IMMUNOTHERAPY ,CHRONIC lymphocytic leukemia treatment - Abstract
A main effector mechanism of rituximab (RTX) is the induction of complement-dependent cytotoxicity (CDC). However, this effector function is limited, because CLL cells are protected from complement-induced damage by regulators of complement activation (RCAs). A prominent RCA in fluid phase is factor H (fH), which has not been investigated in this context yet. Here, we show that fH binds to CLL cells and that human recombinant fH-derived short-consensus repeat 18-20 (hSCR18-20) interferes with this binding. In complement-based lysis assays, CLL cells from therapy-naive patients were differently susceptible to RTX-induced CDC and were defined as CDC responder or CDC non-responder, respectively. In CDC responders, but notably also in non-responders, hSCR18-20 significantly boosted RTX-induced CDC. Killing of the cells was specific for CD20
+ cells, whereas CD20− cells were poorly affected. CDC resistance was independent of expression of the membrane-anchored RCAs CD55 and CD59, although blocking of these RCAs further boosted CDC. Thus, inhibition of fH binding by hSCR18-20 sensitizes CLL cells to CDC and may provide a novel strategy for improving RTX-containing immunochemotherapy of CLL patients. [ABSTRACT FROM AUTHOR]- Published
- 2013
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