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in Multiple Sclerosis Patients 1
,
* Jacobs Neurological Institute, Buffalo General Hospital, Buffalo, NY 14203; Departments of
Pharmaceutical Sciences and
Pathology, State University of New York, Buffalo, NY 14260; and
Department of Statistics, The Cooper Institute, Golden, CO 80401
The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-
-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 µg of IFN--1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN--1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1–4 h of IFN- treatment. The mRNAs for several genes involved in IFN- signaling, such as IFN-
/ receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9–27), IFN-induced transmembrane protein 2 (1–8D), 2-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN- treatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy.
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