RESUMEN
OBJECTIVE: To determine the effect of treatment with interferon beta-1b (IFN-beta) on natural killer (NK) cell function and phenotype in relapsing-remitting MS (RRMS) patients, and their relationship to disease activity assessed both clinically and with serial MRI. BACKGROUND: NK cells may play a role in the immunopathogenesis of MS. Previously the authors reported a positive relationship between mean NK cell functional activity (FA) and total number of active lesions on MRI in a serial study of RRMS. Cycles in NK cell FA over time created a series of peaks and valleys, and a significant relationship has been identified between the valleys and the appearance of active lesions on MRI or onset of clinical attacks. The development of valleys in NK cell FA before the appearance of active lesions on MRI was statistically significant. METHODS: The authors studied the effect of alternate-day therapy with 8.0 mIU (high dose [HD]) or 1.6 mIU (low dose [LD]) IFN-beta on NK cell FA, assessed by an in vitro 51Cr release K-562 target cell assay, and phenotype determination in RRMS patients. RESULTS: Treatment with HD IFN-beta results in an inverse relationship between mean NK cell FA and total number of active lesions on MRI over 2 years. A stronger inverse relationship was found in those patients who did not develop neutralizing antibodies to IFN (HD-) compared with a positive relationship in those who did (HD +). Treatment with IFN-beta did not affect the cyclic nature of NK cell FA, mean NK cell FA, variability around the mean, mean length of the cycle, time spent in valleys and peaks, or the significant relationship between the appearance of active lesions on MRI/onset of clinical attacks and valleys in NK cell FA. In contrast, treatment with HD but not LD IFN-beta did result in a significant reduction in CD57+ (a cell surface marker for subsets of NK cells) peripheral blood lymphocytes (PBL) compared with placebo. This effect, which originated largely from the HD- group of patients, developed shortly after treatment was initiated and was maintained throughout the study. CONCLUSIONS: RRMS patients with higher mean NK cell FA may be not only at greater risk for the development of active lesions but also may be more likely to respond to IFN-beta. Development of neutralizing antibodies to IFN-beta could interfere with this effect. This effect may be mediated through an action on a CD57+ subset of PBL.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Inducción de Remisión/métodos , Adulto , Método Doble Ciego , Femenino , Citometría de Flujo , Humanos , Interferón beta-1a , Interferon beta-1b , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/inmunología , Fenotipo , Proteínas Recombinantes/uso terapéutico , RecurrenciaRESUMEN
Seventeen relapsing-remitting (R/R) multiple sclerosis (MS) patients and age/sex matched controls were studied every 6 weeks for 2 years. Disease activity, determined both clinically and by serial MRI, was correlated with natural killer (NK) cell functional activity (FA) and phenotype. Mean NK cell FA is significantly lower in MS patients, compared to controls (P < 0.001), while variability around the means is significantly greater (P < 0.01). The spectrum of mean NK cell FA, observed in the patient cohort, along with cyclical nature of the FA and phenotype over time, observed in both patients and controls, may begin to explain the discrepant results reported in previous studies. In R/R MS, there is a significant correlation between reductions (valleys) in NK cell FA and the development of active lesions on MRI, new (P < 0.001) or enlarging (P = 0.05). More importantly, a significant number of active lesions, new (P = 0.01) and enlarging (P = 0.02), are preceded by a reduction in NK cell FA. The correlation between the onset of clinical attacks and valleys of NK cell FA is also significant (P = 0.002). When taken together, the results suggest that reductions (valleys) in NK cell FA represent periods of susceptibility for the development of active lesions on MRI and clinical attacks. A significant positive correlation is also identified between mean NK cell FA for each R/R MS patient and total number of active MRI lesions developed by that patient over the 2 years (P = 0.001). The results would suggest that R/R MS patients with a higher mean NK cell FA are at greater risk for the development of active lesions. These results support the proposal that NK cells may play a role in the immunopathogenesis of R/R MS.
Asunto(s)
Células Asesinas Naturales/inmunología , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Adulto , Radioisótopos de Cromo , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/diagnóstico , RecurrenciaRESUMEN
Natural killer (NK) cell functional activity, as defined by the lysis of 51Cr-labelled K-562 cells, and number, defined phenotypically by anti-Leu-11, are significantly decreased in chronic progressive multiple sclerosis (MS) when compared to normal controls. When age- and sex-matched populations are compared, NK cell functional activity is again significantly reduced in MS compared to controls but not when compared to a control group of other medical disease (OMD). The MS group could be differentiated from the OMD group, however, when results of NK cell functional activity are combined with NK cell phenotype. With the administration of lymphoblastoid interferon daily for 6 months, NK cell activity increased significantly at 48 h and at 1 week. By 1 month, activity decreased to a level slightly above placebo treatment values. The results likely reflect interferon's enhancement of mature NK cell activity combined with a variable effect on recruitment of pre-NK cells.