Active MRI lesion appearance in MS patients is preceded by fluctuations in circulating T-helper 1 and 2 cells
Introduction
Evidence has accumulated that in multiple sclerosis (MS), the disease process is mediated by inflammatory events in the central nervous system (CNS). However, the triggering event is still largely unknown, thus generating contradictory hypotheses on the etiopathogenesis of the disease (Martino et al., 2000). A CNS origin of the disease (virus?) is challenged by the ‘peripheral’ hypothesis, which attributes the origin of the disease to an immune-mediated process based on the peripheral reactivation of myelin specific T cells belonging to the ‘normal’ autoimmune repertoire (Martino et al., 2000). The role of activated CD4+ T cells, which have a central role in immunoregulation and are abundantly present in the CNS of MS patients (Traugott et al., 1983), has been extensively studied. After priming, T-helper (Th) cells can maturate into functionally different subsets that can be distinguished by cytokine secretion ability Bottomly, 1988, Navikas and Link, 1996. A distinction can be made between cytokines with pro-inflammatory properties such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, produced by Th1 cells, and cytokines with anti-inflammatory properties like interleukin (IL)-4 and IL-10, produced by Th2 cells (Romagnani, 1991). As postulated for other autoimmune diseases, disease activity in the initial stage of MS is believed to be dependent on activation of Th1 type cells, which is insufficiently counterbalanced by Th2 type cells (Charlton and Lafferty, 1995). In line with this, some evidence has been presented, though controversial, showing that TNF-α promotes disease progression in MS Rieckmann et al., 1995, Van Oosten et al., 1998, while IL-10 might attenuate the disease process Van Boxel-Dezaire et al., 1999, Rieckmann et al., 1994.
MS can manifest itself in different ways, but, particularly in the early phases, patients experience frequent relapses, followed by periods in which the disease follows a more or less stable pattern. Periods of enhanced disease activity have been found to be associated with enhanced levels or secretion of pro-inflammatory cytokines Rieckmann et al., 1995, Van Oosten et al., 1998, Van Boxel-Dezaire et al., 1999, while in stable phases anti-inflammatory cytokines predominate (Rieckmann et al., 1994). However, the relevance of many studies is hampered by their cross-sectional design. In addition, in most studies only clinical parameters of disease activity have been used, while presently the availability of MRI techniques has led to more sensitive markers of disease activity. Of the very few longitudinal studies which correlated immunological parameters to serial MRI in MS, one early study demonstrated that changes in natural killer cell function, immunoglobulin G secretion in vitro, and concanavalin A-induced suppression correlated well with the activity of the disease as recognized by MRI (Oger et al., 1988). A more recent longitudinal study showed that MS patients had increased levels of IL-12p40 mRNA during the development of active lesions (Van Boxel-Dezaire et al., 1999).
We wanted to analyze how disease activity longitudinally relates to phenotypical and functional characteristics of circulating T cells. We therefore investigated how changes in immune measurements are related to clinical exacerbations and to the occurrence of active lesions detected by MRI in untreated MS patients.
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Patients
Analyses were carried out on patients enrolled at the Department of Neurology, VU Medical Center, Amsterdam, the Netherlands in a multicenter, randomized, double-blind, placebo-controlled exploratory phase II trial of the CD4 mAb cM-T412. Detailed information on the design and the efficacy analysis of the trial are described elsewhere (Van Oosten et al., 1997). The 13 MS patients who were analyzed in this study were the Amsterdam placebo controls of this trial. Patient characteristics are given
Differences in overall immune measurements between clinically active and stable MS patients
Compared to patients with clinical disease exacerbation(s) during follow-up, the percentage of T cells producing IFN-γ was increased (p<0.05) in clinically stable patients (mean value of 10 monthly samples per patient, see Table 2). No other overall differences in immune measurements between clinically active and stable MS patients were observed (see Table 2).
Differences in overall immune measurements between patients with and without active MRI lesions during follow-up
Compared to patients with active MRI lesions during follow-up, the percentage and numbers of T cells producing IFN-γ (p<0.01 and p<0.05,
Discussion
In this exploratory study, a transient decrease of both circulating T cells producing IFN-γ and T cells producing IL-4 was found in association with MRI-documented disease activity in MS patients. While the balance between Th1 and Th2 type cells often has been associated with disease progression in MS, thus far no definite conclusions can be drawn from studies on the momentary relationship between parameters of disease activity and production of the typical Th1 and Th2 type cytokines, IFN-γ and
Acknowledgements
This study was supported by Grant 94-192 from the Dutch Society for Support of Research on Multiple Sclerosis.
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