Asunto(s)
Linfoma/terapia , Acondicionamiento Pretrasplante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/uso terapéutico , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lomustina/uso terapéutico , Linfoma/mortalidad , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Terapia Recuperativa/métodos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/mortalidad , Acondicionamiento Pretrasplante/normas , Trasplante AutólogoRESUMEN
Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or agonistic anti-Fas monoclonal antibodies results in the cleavage and activation of the cysteine protease procaspase 8 followed by the activation of procaspase 3 and by apoptosis. In some leukemia cell lines, cytotoxic drugs induce expression of Fas-L, which may contribute to cell killing through the ligation of Fas. The involvement of Fas, Fas-L, and caspase 8 was studied in the killing of B-cell chronic lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or gamma radiation. Spontaneous apoptosis was observed at 24-hour incubation, with additional apoptosis induced by each of the cytotoxic treatments. Although Fas mRNA expression was elevated after exposure to chlorambucil, fludarabine, or gamma radiation, Fas protein levels only increased after irradiation. Therefore, Fas expression may be regulated by multiple mechanisms that allow the translation of Fas mRNA only in response to restricted cytotoxic stimuli. None of the cytotoxic stimuli studied here induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) did not significantly augment apoptosis induction by any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit spontaneous, chlorambucil-, fludarabine-, or radiation-induced apoptosis. However, procaspase 8 processing was induced by all cytotoxic stimuli. These data suggest that the Fas/Fas-L signaling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic drugs or radiation. However, Fas-independent activation of caspase 8 may play a crucial role in the regulation of apoptosis in these cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Caspasas/farmacología , Leucemia Linfocítica Crónica de Células B/patología , Transducción de Señal , Receptor fas/farmacología , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Apoptosis/fisiología , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Linfocitos B/efectos de la radiación , Caspasa 8 , Caspasa 9 , Caspasas/metabolismo , Interacciones Farmacológicas , Activación Enzimática , Proteína Ligando Fas , Femenino , Rayos gamma , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/radioterapia , Masculino , Glicoproteínas de Membrana/análisis , Receptor fas/análisis , Receptor fas/inmunologíaAsunto(s)
Leucemia de Células Pilosas/diagnóstico , Púrpura Trombocitopénica/diagnóstico , Neoplasias del Bazo/diagnóstico , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Leucemia de Células Pilosas/patología , Leucemia de Células Pilosas/fisiopatología , Púrpura Trombocitopénica/patología , Púrpura Trombocitopénica/fisiopatología , Neoplasias del Bazo/patología , Neoplasias del Bazo/fisiopatologíaRESUMEN
The role of the A and E molecules as restriction elements was examined in the F antigen system. In the mouse the only responder haplotype known to date is k, and blocking studies with a monoclonal antibody show that in vitro T-cell proliferation is restricted by the Ak molecule. The (CBA X DBA/2)F1 hybrid, which is a responder X nonresponder cross, is itself a nonresponder in terms of F-specific antibody production. Up to 10 days after priming, (CBA X DBA/2)F1 T cells exhibited an F-specific proliferative response, but this diminished rapidly at later times. This diminution could be blocked with an E-specific monoclonal antibody, suggesting that suppression is restricted by the E molecule.