Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients

Interferon (IFN)-beta has been shown to favorably alter the disease course of relapsing-remitting multiple sclerosis (RRMS) patients. Although its mod e of action is still unclear, there is ample evidence from in vitro studies that IFN-beta directly modulates the function of immune cells. We analyzed here the effects of IFN-beta treatment on immune functions in vivo in a gr oup of 25 RRMS patients who received IFN-beta (8 MIU) on alternate days. At baseline and at 1, 3 and 6 months from the start of the treatment, paramet ers for differentiation and activation states of both monocytes and T lymph ocytes were assessed. A transient increase was seen in plasma (p) interleuk in (IL)-10 level whereas pIL-12 (p40) was not affected. A similar change wa s found in the ability of monocytes to secrete these cytokines in vitro. No tably, patients who in vitro readily responded to IFN-beta with enhanced IL -10 production had the highest pIL-10 levels. Concerning T-cell differentia tion, flowcytometric analysis of cytokine production showed that treatment with IFN-beta moderately decreased the mean percentages of CD8(pos) T cells producing IL-2 and IFN-gamma and CD8(neg) T cells producing IL-4 (p < 0.05 for all cytokines), whereas a more significant decline was seen in the mea n percentage of CD8(neg) T cells producing IFN-gamma (p < 0.01). This resul ted in a significant lower ratio T-HELPER(H)1 vs. T-HELPER(H)2 type cells i n the CD8(pos) T-cell subset (p < 0.05); but not in the CD8(neg) T-cell sub set. Finally, IFN-beta treatment resulted in an initial rise in the mean pe rcentage of CD95(pos) T cells and in a gradual increase in the mean level o f soluble CD95 (sCD95) in plasma (p < 0.01). Additional in vitro studies sh owed that IFN-beta indeed rapidly (within 24 h) upregulates CD95 expression on both primed and unprimed T cells and augments the release of sCD95 in c ulture supernatants. Thus, we confirm here that IFN-beta treatment leads to similar changes in cytokine production of T cells and monocytes as previou sly described in vitro. Enhanced IL-10 secretion may downmodulate cytokine secretion by activated T cells and in this way dampen newly-induced and/or ongoing immune responses. In addition, we identified a novel effect of IFN- beta treatment, i.e., induction of CD95 expression. The augmentation of CD9 5 expression may directly interfere with T-cell selection, notably of autoa ggressive T cells. Future studies are needed to show whether this increased CD95 expression indeed leads to increased apoptosis of immune cells. (C) 1 999 Elsevier Science B.V. All rights reserved.