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Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes.
Sica, Michela; Rondelli, Tommaso; Ricci, Patrizia; De Angioletti, Maria; Risitano, Antonio M; Notaro, Rosario.
Afiliación
  • Sica M; Laboratory of Cancer Genetics and Gene Transfer, Core Research Laboratory - Istituto Toscano Tumori (CRL-ITT), AOU Careggi, viale Pieraccini 6, 50139, Florence, Italy.
  • Rondelli T; Laboratory of Cancer Genetics and Gene Transfer, Core Research Laboratory - Istituto Toscano Tumori (CRL-ITT), AOU Careggi, viale Pieraccini 6, 50139, Florence, Italy.
  • Ricci P; Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
  • De Angioletti M; Laboratory of Cancer Genetics and Gene Transfer, Core Research Laboratory - Istituto Toscano Tumori (CRL-ITT), AOU Careggi, viale Pieraccini 6, 50139, Florence, Italy.
  • Risitano AM; ICCOM-CNR, Sesto Fiorentino, Florence, Italy.
  • Notaro R; Hematology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
J Hematol Oncol ; 10(1): 126, 2017 06 19.
Article en En | MEDLINE | ID: mdl-28629435
BACKGROUND: C5 blockade by eculizumab prevents complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). However, C3-bound PNH red blood cells (RBCs), arising in almost all treated patients, may undergo extravascular hemolysis reducing clinical benefits. Despite the uniform deficiency of CD55 and of CD59, there are always two distinct populations of PNH RBCs, with (C3+) and without (C3-) C3 binding. METHODS: To investigate this paradox, the phenomenon has been modeled in vitro by incubating RBCs from eculizumab untreated PNH patients with compatible sera containing eculizumab, and by assessing the C3 binding after activation of complement alternative pathway. RESULTS: When RBCs from untreated patients were exposed in vitro to activated complement in the context of C5-blockade, there was the prompt appearance of a distinct C3+ PNH RBC population whose size increased with time and also with the rate of complement activation. Eventually, all PNH RBCs become C3+ to the same extent, without differences between old and young (reticulocytes) PNH RBCs. CONCLUSIONS: This study indicates that the distinct (C3+ and C3-) PNH RBC populations are not intrinsically different; rather, they result from a stochastic all-or-nothing phenomenon linked to the time-dependent cumulative probability of each individual PNH red cell to be exposed to levels of complement activation able to trigger C3 binding. These findings may envision novel approaches to reduce C3 opsonization and the subsequent extravascular hemolysis in PNH patients on eculizumab.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C3 / Activación de Complemento / Eritrocitos / Anticuerpos Monoclonales Humanizados / Hemoglobinuria Paroxística / Hemólisis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Hematol Oncol Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Complemento C3 / Activación de Complemento / Eritrocitos / Anticuerpos Monoclonales Humanizados / Hemoglobinuria Paroxística / Hemólisis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Hematol Oncol Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2017 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido