Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA,TRAIL and XAF-1

Abstract

Biological activity of interferon-beta (IFNβ) can be assessed by measuring IFN-stimulated genes (ISGs). Among them, myxovirus resistance protein A (MxA) appears to have the highest specificity, but it has no role in the pathogenesis of multiple sclerosis (MS). To investigate the reliability of MxA as a biomarker, we compared its expression to that of two other ISGs: TNF-related apoptosis-inducing ligand (TRAIL) and X-linked inhibitor of apoptosis factor-1 (XAF-1). Both were shown to be involved in immunoregulatory mechanisms and might play a role in MS. Quantitative-PCR measurements were performed in peripheral blood mononuclear cells from 73 MS patients after short-term and long-term treatment with IFNβ. A time-dependent response for multiple ISGs was observed in all patients after short-term treatment. In contrast, long-term treatment induced concurrent inhibition of ISGs in 12.3% (9/73) of patients, in whom neutralizing antibodies (NAbs) were detectable. Besides, 22% (16/73) of chronically treated patients showed a non-NAbs-related abrogation of TRAIL expression. In summary, 1) MxA expression was significantly higher than both TRAIL and XAF-1, and 2) MxA was the most sensitive gene to detect decreased bioavailability due to NAbs. These findings identify MxA as an appropriate biomarker for IFNβ, although there is no evidence for a functional role of it in MS.

Keywords

biomarkers interferon-beta interferon-stimulated-genes ISG MxA TRAIL XAF-1

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References

Staeheli P , Pavlovic J. Inhibition of vesicular stomatitis virus mRNA synthesis by human MxA protein . J Virol 1991; 65: 4498-4501 .

de Veer MJ , Holko M , Frevel M , Walker E , Der S , Paranjape JM et al. Functional classification of inter-feron-stimulated genes identified using microarrays . J Leukoc Biol 2001; 69: 912-920 . Review.

von Wussow P , Jakschies D , Hochkeppel HK , Fibich C , Penner LM , Deicher H. The human intra-cellular Mx-homologous protein is specifically induced by type I interferons . Eur J Immunol 1990; 20: 2015-2019 .

Deisenhammer F , Reindel M , Harvey J , Gasse T , Dilitz E , Berger T. Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies . Neurology 1999; 52: 1239-1243 .

Kracke A , von Wussow P , Al-Masri AN , Dalley G , Windhagen A , Heidenreich F. Mx proteins in blood leukocytes for monitoring interferon beta-1b therapy in patients with MS . Neurology 2000; 54: 193-199 .

Vallittu AM , Halminen M , Peltoniemi J , Ilonen J , Julkunen I , Salmi A et al. Neutralizing antibodies reduce MxA protein induction in interferon-beta 1a-treated MS patients . Neurology 2001; 58: 1786-1790 .

Pachner AR , Narayan K , Price N , Hurd M , Dail D. MxA gene expression analysis as an interferon-b bioactivity measurement in patients with multiple sclerosis and the identification of antibody-mediated decreased bio-activity . Mol Diagn 2003; 7: 17-25 .

Bertolotto A , Gilli F , Sala A , Audano L , Castello A , Magliola U et al. Evaluation of bioavailability of three types of IFNβ in multiple sclerosis patients by a new quantitative-competitive-PCR method for MxA quantification . J Immunol Methods 2001; 256: 141-152 .

Bertolotto A , Gilli F , Sala A , Capobianco M , Malucchi S , Milano E et al. Persistent neutralizing antibodies abolish the interferon-b bioavailability in MS patients . Neurology 2003; 60: 634-639 .

10.

Bertolotto A , Sala A , Malucchi S , Marnetto F , Caldano M , Di Sapio A et al. Biological activity of interferon betas in patients with multiple sclerosis is affected by treatment regimen and neutralising antibodies . J Neurol Neurosurg Psychiatry 2004; 75: 1294-1299 .

11.

Gilli F , Sala A , Bancone C , Salacone P , Gallo M , Gaia E et al. Evaluation of IFNa bioavailability by MxA mRNA in HCV patients . J Immunol Methods 2002; 262: 183-186 .

12.

Gilli F , Bertolotto A , Sala A , Hoffmann F , Capo-bianco M , Malucchi S et al. Neutralising antibodies against IFN-b in MS: antagonisation of IFN-b mediated suppression of MMPs . Brain 2004; 127: 259-268 .

13.

Gilli F , Marnetto F , Caldano M , Sala A , Malucchi S , Di Sapio A et al. Biological responsiveness to first injections of interferon-beta in patients with multiple sclerosis . J Neuroimmunol 2005; 158: 195-203 .

14.

Horisberger MA. Interferon-induced human protein MxA is a GTPase which binds transiently to cellular proteins . J Virol 1992; 66: 4705-4709 .

15.

Haller O , Kochs G. Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity . Traffic 2002; 3: 710-717 . Review.

16.

Wiley SR , Schooley K , Smolak PJ , Din WS , Huang CP , Nicholl JK et al. Identification and characterization of a new member of the TNF family that induces apoptosis . Immunity 1995; 3: 673-682 .

17.

Chawla-Sarkar M , Leaman DW , Borden EC. Preferential induction of apoptosis by interferon (IFN)-beta compared with IFN-alpha2: correlation with TRAIL/Apo2L induction in melanoma cell lines . Clin Cancer Res 2001; 7: 1821-1831 .

18.

Wandinger KP , Lunemann JD , Wengert O , Bellmann-Strobl J , Aktas O , Weber A et al. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis . Lancet 2003; 361: 2036-2043 .

19.

Song K , Chen Y , Goke R , Wilmen A , Seidel C , Goke A et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression . J Exp Med 2000; 191: 1095-1104 .

20.

Wendling U , Walczak H , Dorr J , Jaboci C , Weller M , Krammer PH et al. Expression of TRAIL receptors in human autoreactive and foreign antigen-specific T cells . Cell Death Differ 2000; 7: 637-644 .

21.

Chawla-Sarkar M , Lindner DJ , Liu YF , Williams BR , Sen GC , Silverman RH et al. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis . Apoptosis 2003; 8: 237-249 . Review.

22.

McDonald WI , Compston A , Edan G , Goodkin D , Hartung HP , Lublin FB et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis . Ann Neurol 2001; 50: 121-127 .

23.

Antonelli G , Bagnato F , Pozzilli C , Simeoni E , Bastianelli S , Currenti M et al. Development of neutralizing antibodies in patients with relapsing-remitting multiple sclerosis treated with IFN-b1a . J Interferon Cytokine Res 1998; 18: 345-350 .

24.

Bertolotto A , Malucchi S , Milano E , Castello A , Capobianco M , Mutani R. Interferon-beta neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations . Immunopharmacology 2000; 48: 95-100 .

25.

WHO Expert Committee on Biological Standardisation . Thirty-fifth report. WHO Technical Report Series 725. Geneva: World Health Organization , 1985.

26.

Grossberg SE , Kawade Y. The expression of potency of neutralizing antibodies for interferon and other cytokines . Biotherapy 1997; 10: 93-98 .

27.

Grossberg SE , Kawade Y , Kohase M , Yokoyama H , Finter N. The neutralization of interferons by antibody: I. Quantitative and theoretical analyses of the neutralization reaction in different bioassay systems . J Interferon Cytokine Res 2001; 21: 729-742 .

28.

Kawade Y. Quantitation of neutralization of interferon by antibodies . Methods Enzymol 1986; 119: 558-573 .

29.

Grossberg SE , Kawade Y , Kohase M , Yokoyama H , Finter N. The neutralization of interferons by antibody. II. Neutralizing antibody unitage and its relationship to bioassay sensitivity: the tenfold reduction unit . J Inter-feron Cytokine Res 2003; 21: 743-755 .

30.

Gibson UE , Heid CA , Williams PM. A novel method for real time quantitative RT-PCR . Genome Res 1996; 6: 995-1001 .

31.

Schumacher GA , Beebe GW , Kibler RF , Kurland LT , Kurtzke JF , McDowell F et al. Problems of experimental trials of therapy in multiple sclerosis . Ann NY Acad Sci 1965; 122: 552-568 .

32.

Hong J , Zang YC , Hutton G , Rivera VM , Zhang JZ. Gene expression profiling of relevant biomarkers for treatment evaluation in multiple sclerosis . J Neuroimmunol 2004; 152: 126-139 .

33.

Kamohara H , Matsuyama W , Shimozato O , Abe K , Galligan C , Hashimoto S et al. Regulation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor expression in human neutrophils . Immunology 2004; 111: 186-194 .

34.

Abdollahi T , Robertson NM , Abdollahi A , Litwack G. Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OCCAR3 . Cancer Res 2003; 63: 4521-4526 .

35.

Kahl KG , Kruse N , Toyka KV , Rieckmann P. Serial analysis of cytokine mRNA profiles in whole blood samples from patients with early multiple sclerosis . J Neurol Sci 2002; 200: 53-55 .

36.

Ruiz de Almodovar C , Lopez-Rivas A , Ruiz-Ruiz C. Interferon-gamma and TRAIL in human breast tumor cells . Vitam Horm 2004; 67: 291-318 . Review.

37.

Park SY , Seol JW , Lee YJ , Cho JH , Kang HS , Kim IS et al. IFN-gamma enhances TRAIL-induced apoptosis through IRF-1 . Eur J Biochem 2004; 271: 4222-4228 .

38.

Sorensen PS , Ross C , Clemmesen KM , Bendtzen K , Frederiksen JL , Jensen K et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis . Lancet 2003; 362: 1184-1191 .

39.

Malucchi S , Sala A , Gilli F , Bottero R , Di Sapio A , Capobianco M et al. Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis . Neurology 2004; 62: 2031-2037 .

40.

Perini P , Calabrese M , Biasi G , Gallo P. The clinical impact of interferon beta antibodies in relapsing-remitting MS . J Neurol 2004; 251: 305-309 .

41.

Petkau AJ , White RA , Ebers GC , Reder AT , Sibley WA , Lublin FD et al. Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis . Mult Scler 2004; 10: 126-138 .

42.

Matusevicius D , Kivisakk P , Navikas VV , Tian W , Soderstrom M , Fredrikson S et al. Influence of IFN-beta1b (Betaferon) on cytokine mRNA profiles in blood mononuclear cells and plasma levels of soluble VCAM-1 in multiple sclerosis . Eur J Neurol 1998; 5: 265-275 .

43.

Rudick AR. Biological impact of interferon antibodies and complexities in assessing their clinical significance . Neurology 2003; 61: S31-S34 . Review.

44.

The PRISMS (Prevention of Relapses and Disability by Interferon-b-1a Subcutaneously in Multiple Sclerosis) Study Group and the University of British Columbia MS/MRI Analysis Group . PRISMS-4: long-term efficacy of interferon-b-1a in relapsing MS . Neurology 2001; 56: 1628-1636 .

45.

Polman C , Kappos L , White R , Dahlke F , Beck-mann K , Pozzilli C et al. Neutralizing antibodies during treatment of secondary progressive MS with interferon-b-1b . Neurology 2003; 60: 37-43 .

46.

Sturzebecher S , Wandinger KP , Rosenwald A , Sathyamoorthy M , Tzou A , Mattar P et al. Expression profiling identifies responder and non-responder phenotypes to interferon-beta in multiple sclerosis . Brain 2003; 126: 1419-1429 .