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
Restricted accessOtherFirst published online March, 2008
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
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
Sospedra M., Martin R.Immunology of multiple sclerosis. Annu Rev Immunol2005; 23: 683—747.
2.
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. Lancet1998; 352: 1498—1504.
3.
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 Neurol1996; 39: 285—94.
4.
Paty DW, Li DKInterferon beta-lb is effective in relapsingremitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. 1993 [classical article]. Neurology2001; 57: S10—15.
5.
Hartung HP, Bar-Or A., Zoukos Y.What do we know about the mechanism of action of disease-modifying treatments in MS?J Neurol2004; 251 (Suppl 5): v12—29.
6.
Chitnis T., Khoury SJRole of costimulatory pathways in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. J Allergy Clin Immunol2003; 112: 837—49.
7.
Greenwald RJ , Freeman GJ, Sharpe AHThe B7 family revisited. Annu Rev Immunol2005; 23: 515—48.
8.
Racke MK, Ratts RB, Arredondo L., Perrin PJ, Lovett-Racke A.The role of costimulation in autoimmune demyelination. J Neuroimmunol2000; 107: 205—15.
9.
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 Med1995; 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 Neuroimmunol1999; 96: 112—20.
11.
Monteyne P. , Guillaume B., Sindic CJB7-1 (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 Neuroimmunol1998; 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 Neuroimmunol1997; 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 USA1996; 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 Immunol2004; 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 Immunol2001 ; 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 Immunol2001; 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 Immunol2003 ; 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 Med2003; 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 Neurol2005; 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 Neuroimmunol2004; 155: 172—82.
21.
Pachner ARAn improved ELISA for screening for neutralizing anti-IFN-beta antibodies in MS patients. Neurology2003; 61: 1444—6.
22.
Hong J., Zang YC, Hutton G., Rivera VM, Zhang JZGene expression profiling of relevant biomarkers for treatment evaluation in multiple sclerosis. J Neuroimmunol2004 ; 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 Neuroimmunol2003 ; 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. Brain2003; 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 Neuroimmunol2002 ; 123: 160—9.
26.
Noronha A., Toscas A., Jensen MAInterferon beta decreases T-cell activation and interferon gamma production in multiple sclerosis. J Neuroimmunol1993 ; 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 Immunol2000; 165: 548—7.
28.
Genc K., Dona DL, Reder ATIncreased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy. J Clin Invest1997; 99: 2664—71.
29.
Liu Z., Pelfrey CM, Cotleur A., Lee JC, Rudick RAImmunomodulatory effects of interferon beta-1a in multiple sclerosis. J Neuroimmunol2001; 112: 153—62.
30.
Filion LG, Matusevicius D., Graziani-Bowering GM, Kumar A., Freedman MSMonocyte-derived IL12, CD86 (B7-2) and CD40L expression in relapsing and progressive multiple sclerosis. Clin Immunol2003; 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 Med1999 ; 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 . Immunity1999; 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 Med2000; 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 Immunol2001 ; 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 USA2004; 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 Invest2003 ; 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 Med2001; 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 Med2003; 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. Lancet2003; 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 Scler2005; 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 Neuroimmunol2004; 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 Neuroimmunol2005; 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 Neuroimmunol2004; 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 Neurol2000; 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. Neurology1998; 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 Neurosurg2006; 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 Neurol2005; 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 Neurol2001; 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 Scler2005; 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 Neuroimmunol2003; 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 Scand2004; 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 Scler2004 ; 10: 281—3.
