title: Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients.
abstract: Interferon (IFN)-beta has been shown to favorably alter the disease course of relapsing-remitting multiple sclerosis (RRMS) patients. Although its mode 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 group 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, parameters for differentiation and activation states of both monocytes and T lymphocytes were assessed. A transient increase was seen in plasma (p) interleukin (IL)-10 level whereas pIL-12 (p40) was not affected. A similar change was found in the ability of monocytes to secrete these cytokines in vitro. Notably, patients who in vitro readily responded to IFN-beta with enhanced IL-10 production had the highest pIL-10 levels. Concerning T-cell differentiation, flow cytometric analysis of cytokine production showed that treatment with IFN-beta moderately decreased the mean percentages of CD8pos T cells producing IL-2 and IFN-gamma and CD8neg T cells producing IL-4 (p<0.05 for all cytokines), whereas a more significant decline was seen in the mean percentage of CD8neg T cells producing IFN-gamma (p<0.01). This resulted in a significant lower ratio T(HELPER(H))1 vs. T(HELPER(H))2 type cells in the CD8pos T-cell subset (p<0.05), but not in the CD8neg T-cell subset. Finally, IFN-beta treatment resulted in an initial rise in the mean percentage of CD95pos T cells and in a gradual increase in the mean level of soluble CD95 (sCD95) in plasma (p<0.01). Additional in vitro studies showed 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 culture supernatants. Thus, we confirm here that IFN-beta treatment leads to similar changes in cytokine production of T cells and monocytes as previously 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 CD95 expression may directly interfere with T-cell selection, notably of autoaggressive T cells. Future studies are needed to show whether this increased CD95 expression indeed leads to increased apoptosis of immune cells.
authors.affiliation: Department of Clinical Viro-Immunology, CLB, Academic Medical Centre, University of Amsterdam, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Rep
authors.forename: H M
authors.initials: HM
authors.lastname: Schrijver
authors.forename: T
authors.initials: T
authors.lastname: van Lopik
authors.forename: R Q
authors.initials: RQ
authors.lastname: Hintzen
authors.forename: M T
authors.initials: MT
authors.lastname: Roos
authors.forename: H J
authors.initials: HJ
authors.lastname: Adèr
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: R A
authors.initials: RA
authors.lastname: van Lier
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000097:blood* / Q000378:metabolism; D018664:Interleukin-12 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D037181:Lectins, C-Type; D008297:Male; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D011994:Recombinant Proteins / Q000008:administration & dosage; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000378:metabolism*; D019014:fas Receptor / Q000032:analysis / Q000097:blood*; D000099192:CD69 Antigens
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016899:Interferon-beta; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D007376:Interleukin-2; D015847:Interleukin-4; D037181:Lectins, C-Type; D011994:Recombinant Proteins; D019014:fas Receptor; D000099192:CD69 Antigens