Natural killer cells in relapsing-remitting MS: effect of treatment with
interferon beta-1B.
Kastrukoff LF, Morgan NG, Zecchini D, White R, Petkau AJ, Satoh J, Paty DW
Department of Medicine, University of British Columbia, Vancouver, Canada.
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.
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