RESUMEN
Anti-platelet antibodies are known to contribute to some types of thrombocytopenia. In this work we investigated anti-platelet antibodies with opposite influence upon activation and kinetics of platelet caspases. A rabbit anti-platelet antibody induced a profound thrombocytopenia, which was associated with an increase of microparticles in plasma and an activation of platelet caspases, as detected by the binding of a carboxyfluorescein-labeled fluoromethyl ketone probe (FAM-VAD-fmk). Furthermore, microparticles and thrombocytopenia were prevented by the injection of a caspase inhibitor ZVAD-fmk. In contrast, an anti-CD18 mAb (M18.2) induced a thrombocytosis, due to an increased platelet life-span and which was evident in wild-type (+/+), but not in CD18-/- or CD87-/-, mice indicating a requirement of these two surface molecules. Activation of caspases was decreased in platelets from mice injected with the M 18.2 mAb, as evidenced by a decreased binding of the VAD probe, detected by flow cytometry, or an increase in the level of pro-caspase-3, seen on Western blots. These observations indicate firstly, that anti-platelet antibodies can either promote or inhibit activation of platelet caspases, and secondly, that the activation of caspases regulates platelet life-span.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Plaquetas/inmunología , Antígenos CD18/inmunología , Caspasas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/inmunología , Animales , Plaquetas/citología , Plaquetas/enzimología , Antígenos CD18/genética , Antígenos CD18/fisiología , Caspasas/metabolismo , Activación Enzimática/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/fisiología , Ratones , Ratones Noqueados , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/fisiología , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Trombocitopenia/inducido químicamente , Trombocitopenia/enzimología , Trombocitopenia/inmunologíaRESUMEN
BACKGROUND: The response of tumors to chemotherapy (CHT) exhibits wide individual variations. PATIENTS AND METHODS: We examined the incidence of polymorphic TNF genes in 61 patients treated for Hodgkin lymphoma. RESULTS: During treatment, the patients were divided as responders or non-responders, depending upon the amount of CHT required for a clinical eradication of the tumor. The incidence of TNFa4, a microsatellite allele associated with low TNF production in leukocytes, was significantly higher in responders than in non-responders (25.7% vs 0 %, p=0.04). We also examined the incidence of tumor relapses 2-5 years after treatment. The incidence of TNFa4 was also significantly higher in patients with relapses, than in those without relapses (41.1% vs 9.3%, p=0.007). CONCLUSION: These results indicate that TNFa4 is a marker of resistance of Hodgkin lymphoma to chemotherapy and most probably is a marker of bad prognosis.