Effects of interferon-β on co-signaling molecules: upregulation of CD40,CD86 and PD-L2 on monocytes in relation to clinical response to interferon-β treatment in patients with multiple sclerosis

Abstract

Interferon-beta (IFN-β) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-β is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-β on the expression of co-signaling pathways (CD28—CD80/CD86, CD154—CD40, ICOS—ICOSL, PD-1—PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-β in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-β, and in vivo in whole blood samples of 32 untreated and 24 IFN-β treated MS patients, including 13 patients longitudinal. IFN-β treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4⁺-T-cells in vitro and in vivo. IFN-β treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-β (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-β upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-β in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-β treatment at early timepoints during IFN-β therapy. Multiple Sclerosis 2008; 14: 166—176. http://msj.sagepub.com

Keywords

B7 family co-stimulatory molecules interferon-beta multiple sclerosis PD-L1 PD-L2

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References

Sospedra M. , Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683—747.

PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498—1504.

Jacobs LD , Cookfair DL , Rudick RA , Herndon RM , Richert JR , Salazar AM et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39: 285—94.

Paty DW , Li DK Interferon beta-lb is effective in relapsingremitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology 2001; 57: S10—15.

Hartung HP , Bar-Or A. , Zoukos Y.

What do we know about the mechanism of action of disease-modifying treatments in MS?

J Neurol 2004; 251 (Suppl 5): v12—29.

Chitnis T. , Khoury SJ Role of costimulatory pathways in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. J Allergy Clin Immunol 2003; 112: 837—49.

Greenwald RJ , Freeman GJ , Sharpe AH The B7 family revisited. Annu Rev Immunol 2005; 23: 515—48.

Racke MK , Ratts RB , Arredondo L. , Perrin PJ , Lovett-Racke A. The role of costimulation in autoimmune demyelination. J Neuroimmunol 2000; 107: 205—15.

Windhagen A. , Newcombe J. , Dangond F. , Strand C. , Woodroofe MN , Cuzner ML et al. Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 1995; 182: 1985—96.

10.

Windhagen A. , Maniak S. , Gebert A. , Ferger I. , Heidenreich F. Costimulatory molecules B7-1 and B7-2 on CSF cells in multiple sclerosis and optic neuritis. J Neuroimmunol 1999; 96: 112—20.

11.

Monteyne P. , Guillaume B. , Sindic CJ B7-1 (CD80), B7-2 (CD86), interleukin-12 and transforming growth factor-beta mRNA expression in CSF and peripheral blood mononuclear cells from multiple sclerosis patients. J Neuroimmunol 1998; 91: 198—203.

12.

Svenningsson A. , Dotevall L. , Stemme S. , Andersen O. Increased expression of B7-1 costimulatory molecule on cerebrospinal fluid cells of patients with multiple sclerosis and infectious central nervous system disease. J Neuroimmunol 1997; 75: 59—68.

13.

Gerritse K. , Laman JD , Noelle RJ , Aruffo A. , Ledbetter JA , Boersma WJ et al. CD40-CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 1996; 93: 2499—504.

14.

Marckmann S. , Wiesemann E. , Hilse R. , Trebst C. , Stangel M. , Windhagen A. Interferon-beta up-regulates the expression of co-stimulatory molecules CD80, CD86 and CD40 on monocytes: significance for treatment of multiple sclerosis. Clin Exp Immunol 2004; 138: 499—506.

15.

Rottman JB , Smith T. , Tonra JR , Ganley K. , Bloom T. , Silva R. et al. The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE. Nat Immunol 2001 ; 2: 605—11.

16.

Sporici RA , Beswick RL , von Allmen C. , Rumbley CA , Hayden-Ledbetter M. , Ledbetter JA et al. ICOS ligand costimulation is required for T-cell encephalitogenicity . Clin Immunol 2001; 100: 277—88.

17.

Liang SC , Latchman YE , Buhlmann JE , Tomczak MF , Horwitz BH , Freeman GJ et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003 ; 33: 2706—16.

18.

Salama AD , Chitnis T. , Imitola J. , Ansari MJ , Akiba H. , Tushima F. et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 2003; 198: 71—8.

19.

Kroner A. , Mehling M. , Hemmer B. , Rieckmann P. , Toyka KV , Maurer M. et al. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 2005; 58: 50—7.

20.

Schreiner B. , Mitsdoerffer M. , Kieseier BC , Chen L. , Hartung HP , Weller M. et al. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 2004; 155: 172—82.

21.

Pachner AR An improved ELISA for screening for neutralizing anti-IFN-beta antibodies in MS patients. Neurology 2003; 61: 1444—6.

22.

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—39.

23.

Koike F. , Satoh J. , Miyake S. , Yamamoto T. , Kawai M. , Kikuchi S. et al. Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis. J Neuroimmunol 2003 ; 139: 109—18.

24.

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—29.

25.

Wiesemann E. , Soenmez D. , Heidenreich F. , Windhagen A. Interferon beta increases the stimulatory capacity of monocyte-derived dendritic cells to induce IL-13, IL-5 and IL-10 in autologous T-cells. J Neuroimmunol 2002 ; 123: 160—9.

26.

Noronha A. , Toscas A. , Jensen MA Interferon beta decreases T-cell activation and interferon gamma production in multiple sclerosis. J Neuroimmunol 1993 ; 46: 145—53.

27.

Wang X. , Chen M. , Wandinger KP , Williams G. , Dhib-Jalbut S. IFN-beta-1b inhibits IL-12 production in peripheral blood mononuclear cells in an IL-10-dependent mechanism: relevance to IFN-beta-1b therapeutic effects in multiple sclerosis. J Immunol 2000; 165: 548—7.

28.

Genc K. , Dona DL , Reder AT Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy. J Clin Invest 1997; 99: 2664—71.

29.

Liu Z. , Pelfrey CM , Cotleur A. , Lee JC , Rudick RA Immunomodulatory effects of interferon beta-1a in multiple sclerosis. J Neuroimmunol 2001; 112: 153—62.

30.

Filion LG , Matusevicius D. , Graziani-Bowering GM , Kumar A. , Freedman MS Monocyte-derived IL12, CD86 (B7-2) and CD40L expression in relapsing and progressive multiple sclerosis. Clin Immunol 2003; 106: 127—38.

31.

Dong H. , Zhu G. , Tamada K. , Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999 ; 5: 1365—69.

32.

Nishimura H. , Nose M. , Hiai H. , Minato N. , Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor . Immunity 1999; 11: 141—51.

33.

Freeman GJ , Long AJ , Iwai Y. , Bourque K. , Chernova T. , Nishimura H. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: 1027—34.

34.

Latchman Y. , Wood CR , Chernova T. , Chaudhary D. , Borde M. , Chernova I. et al. PD-L2 is a second ligand for PD-1 and inhibits T-cell activation. Nat Immunol 2001 ; 2: 261—8.

35.

Latchman YE , Liang SC , Wu Y. , Chernova T. , Sobel RA , Klemm M. et al. PD-L1-deficient mice show that PD-L1 on T-cells, antigen-presenting cells, and host tissues negatively regulates T-cells. Proc Natl Acad Sci USA 2004; 101: 10691—6.

36.

Dong H. , Strome SE , Matteson EL , Moder KG , Flies DB , Zhu G. et al. Costimulating aberrant T-cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 2003 ; 111: 163—70.

37.

Tseng SY , Otsuji M. , Gorski K. , Huang X. , Slansky JE , Pai SI et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T-cells. J Exp Med 2001; 193: 839—46.

38.

Liu X. , Gao JX , Wen J. , Yin L. , Li O. , Zuo T. et al. B7DC/PDL2 promotes tumor immunity by a PD-1-independent mechanism . J Exp Med 2003; 197: 1083—91.

39.

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—43.

40.

Avolio C. , Filippi M. , Tortorella C. , Rocca MA , Ruggieri M. , Agosta F. et al. Serum MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios in multiple sclerosis: relationships with different magnetic resonance imaging measures of disease activity during IFN-beta-1a treatment. Mult Scler 2005; 11: 441—6.

41.

Muraro PA , Liberati L. , Bonanni L. , Pantalone A. , Caporale CM , Iarlori C. et al. Decreased integrin gene expression in patients with MS responding to interferon-beta treatment. J Neuroimmunol 2004; 150: 123—31.

42.

Soilu-Hanninen M. , Laaksonen M. , Hanninen A. , Eralinna JP , Panelius M. Downregulation of VLA-4 on T-cells as a marker of long term treatment response to interferon beta-1a in MS. J Neuroimmunol 2005; 167: 175—82.

43.

Fainardi E. , Rizzo R. , Melchiorri L. , Castellazzi M. , Govoni V. , Caniatti L. et al. Beneficial effect of interferon-beta 1b treatment in patients with relapsingremitting multiple sclerosis is associated with an increase in serum levels of soluble HLA-I molecules during the first 3 months of therapy. J Neuroimmunol 2004; 148: 206—11.

44.

Boxel-Dezaire AH , Trigt-Hoff SC , Killestein J. , Schrijver HM , van Houwelingen JC , Polman CH et al. Contrasting responses to interferon beta-1b treatment in relapsing-remitting multiple sclerosis: does baseline interleukin-12p35 messenger RNA predict the efficacy of treatment? Ann Neurol 2000; 48: 313—22.

45.

Rudick RA , Ransohoff RM , Lee JC , Peppler R. , Yu M. , Mathisen PM et al. In vivo effects of interferon beta-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 1998; 50: 1294—1300.

46.

Bartosik-Psujek H. , Stelmasiak Z. The interleukin-10 levels as a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients . Clin Neurol Neurosurg 2006; 108: 644—7.

47.

Wergeland S. , Beiske A. , Nyland H. , Hovdal H. , Jensen D. , Larsen JP et al. IL-10 promoter haplotype influence on interferon treatment response in multiple sclerosis. Eur J Neurol 2005; 12: 171—5.

48.

Laske C. , Oschmann P. , Tofighi J. , Kuhne BS , Diehl H. , Bregenzer T. et al. Prognostic value of soluble tumor necrosis factor receptors 1 and 2 in multiple sclerosis patients treated with interferon beta-1b. Eur Neurol 2001; 46: 210—14.

49.

Sellebjerg F. , Ross C. , Koch-Henriksen N. , Sorensen PS , Frederiksen JL , Bendtzen K. et al. CD26 + CD4 + T-cell counts and attack risk in interferon-treated multiple sclerosis . Mult Scler 2005; 11: 641—5.

50.

Batocchi AP , Rotondi M. , Caggiula M. , Frisullo G. , Odoardi F. , Nociti V. et al. Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta. J Neuroimmunol 2003; 139: 150—4.

51.

Casoni F. , Merelli E. , Bedin R. , Sola P. , Bertolotto A. , Faglioni P. Is serum neopterin level a marker of responsiveness to interferon beta-1a therapy in multiple sclerosis? Acta Neurol Scand 2004; 109: 61—5.

52.

Petzold A. , Brassat D. , Mas P. , Rejdak K. , Keir G. , Giovannoni G. et al. Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis. Mult Scler 2004 ; 10: 281—3.