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From the Division of Neurology, Department of Medicine (Drs. Kastrukoff and Paty, and N.G. Morgan and D. Zecchini), and the Statistical Consulting and Research Laboratory, Department of Statistics (R. White and Dr. Petkau), University of British Columbia, Vancouver, Canada; and the Department of Medicine (Dr. Satoh), Saga Medical College, Japan.
Address correspondence and reprint requests to Dr. Lorne F. Kastrukoff, Division of Neurology, Department of Medicine, Vancouver Hospital & HSC, 2211 Wesbrook Mall, University of British Columbia, Vancouver, BC, Canada V6T-1Z3.
OBJECTIVE: To determine the effect of treatment with interferon ß-1b (IFN-ß) 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-ß 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-ß 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-ß 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-ß 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-ß. Development of neutralizing antibodies to IFN-ß could interfere with this effect. This effect may be mediated through an action on a CD57+ subset of PBL.
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