RESUMO
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.
Assuntos
Anticorpos Monoclonais Murinos/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Ativação do Complemento/imunologia , Citotoxicidade Imunológica/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Antineoplásicos/farmacologia , Western Blotting , Fator H do Complemento/imunologia , Fator H do Complemento/metabolismo , Citometria de Fluxo , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Prognóstico , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Rituximab , Células Tumorais CultivadasRESUMO
We describe a new technique for studying thermally induced chemical transformations in cellulose. The apparatus consists of a carbon dioxide laser for heating, an IR thermometer, and an optical reflectance spectrometer for tracking the progressive discoloration of the sample. To illustrate the technique, we present measurements from a single piece of sample linen along five isotherms in the 200-290 degrees C range. We derive an algebraic expression for the reflectivity of the sample as a function of the areal concentrations of the chromophoric states produced at temperature. The results are then explained in terms of first-order chemical rate theory and a four-step model. From the measurements we derive the activation energies, Arrhenius constants, and reflectivities of the chromophoric states.
