Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients
Tóm tắt
Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months. RRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests. Neopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation. Although differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies.
Tài liệu tham khảo
Javed A, Reder AT: Therapeutic role of beta-interferons in multiple sclerosis. Pharmacol Ther. 2006, 110: 35-56. 10.1016/j.pharmthera.2005.08.011.
Kappos L, Traboulsee A, Constantinescu C, Eralinna JP, Forrestal F, Jongen P, Pollard J, Sandberg-Wollheim M, Sindic C, Stubinski B: Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology. 2006, 67: 944-953. 10.1212/01.wnl.0000237994.95410.ce.
Giovannoni G, Lai M, Kidd D, Thorpe JW, Miller DH, Thompson AJ, Keir G, Feldmann M, Thompson EJ: Daily urinary neopterin excretion as an immunological marker of disease activity in multiple sclerosis. Brain. 1997, 120 (Pt 1): 1-13. 10.1093/brain/120.1.1.
Sorensen PS: Biological markers in body fluids for activity and progression in multiple sclerosis. Mult Scler. 1999, 5: 287-290. 10.1191/135245899678846230.
Bagnato F, Durastanti V, Finamore L, Volante G, Millefiorini E: Beta-2 microglobulin and neopterin as markers of disease activity in multiple sclerosis. Neurol Sci. 2003, 24 (Suppl 5): S301-304. 10.1007/s10072-003-0180-5.
Scagnolari C, Duda P, Bagnato F, De Vito G, Alberelli A, Lavolpe V, Girardi E, Durastanti V, Trojano M, Kappos L, Antonelli G: Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies. J Neurol. 2007, 254: 597-604. 10.1007/s00415-006-0332-7.
Meyer KC, Cornwell R, Carlin JM, Powers C, Irizarry A, Byrne GI, Borden EC: Effects of interferons beta or gamma on neopterin biosynthesis and tryptophan degradation by human alveolar macrophages in vitro: synergy with lipopolysaccharide. Am J Respir Cell Mol Biol. 1992, 6: 639-646.
Amirkhani A, Rajda C, Arvidsson B, Bencsik K, Boda K, Seres E, Markides KE, Vecsei L, Bergquist J: Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients. Eur J Neurol. 2005, 12: 625-631. 10.1111/j.1468-1331.2005.01041.x.
Meager T: The Molecular Biology of Cytokines. 1998, John Wiley & Sons
Carlin JM, Borden EC, Sondel PM, Byrne GI: Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes. J Leukoc Biol. 1989, 45: 29-34.
Adams O, Besken K, Oberdorfer C, MacKenzie CR, Takikawa O, Daubener W: Role of indoleamine-2,3-dioxygenase in alpha/beta and gamma interferon-mediated antiviral effects against herpes simplex virus infections. J Virol. 2004, 78: 2632-2636. 10.1128/JVI.78.5.2632-2636.2004.
Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D: Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2006, 364: 82-90. 10.1016/j.cca.2005.06.013.
Opitz CA, Wick W, Steinman L, Platten M: Tryptophan degradation in autoimmune diseases. Cell Mol Life Sci. 2007, 64: 2542-2563. 10.1007/s00018-007-7140-9.
Fuchs D, Moller AA, Reibnegger G, Stockle E, Werner ER, Wachter H: Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J Acquir Immune Defic Syndr. 1990, 3: 873-876.
Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM: Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1998, 50: 1266-1272.
Bagnato F, Pozzilli C, Scagnolari C, Bellomi F, Pasqualetti P, Gasperini C, Millefiorini E, Galgani S, Spadaro M, Antonelli G: A one-year study on the pharmacodynamic profile of interferon-beta1a in MS. Neurology. 2002, 58: 1409-1411.
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: 61-65. 10.1046/j.1600-0404.2003.00177.x.
Matrisciano F, Bonaccorso S, Ricciardi A, Scaccianoce S, Panaccione I, Wang L, Ruberto A, Tatarelli R, Nicoletti F, Girardi P, Shelton RC: Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatr Res. 2009, 43: 247-254. 10.1016/j.jpsychires.2008.03.014.
Bertolotto A, Gilli F: Interferon-beta responders and non-responders. A biological approach. Neurol Sci. 2008, 29 (Suppl 2): S216-217. 10.1007/s10072-008-0941-2.
Pachner AR, Warth JD, Pace A, Goelz S: Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study. Neurology. 2009, 73: 1493-1500. 10.1212/WNL.0b013e3181bf98db.
Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983, 33: 1444-1452.
Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW: Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005, 58: 840-846. 10.1002/ana.20703.
Munafo A, Trinchard-Lugan II, Nguyen TX, Buraglio M: Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol. 1998, 5: 187-193. 10.1046/j.1468-1331.1998.520187.x.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983, 13: 227-231. 10.1002/ana.410130302.
Widner B, Werner ER, Schennach H, Wachter H, Fuchs D: Simultaneous measurement of serum tryptophan and kynurenine by HPLC. Clin Chem. 1997, 43: 2424-2426.
Laich A, Neurauter G, Widner B, Fuchs D: More rapid method for simultaneous measurement of tryptophan and kynurenine by HPLC. Clin Chem. 2002, 48: 579-581.
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. 10.1089/107999001753124462.
Grossberg SE, Kawade Y, Kohase M, Klein JP: The neutralization of interferons by antibody. II. Neutralizing antibody unitage and its relationship to bioassay sensitivity: the tenfold reduction unit. J Interferon Cytokine Res. 2001, 21: 743-755. 10.1089/107999001753124471.
Kieseier BC, Hartung HP: Bioavailability of interferon-beta in patients with multiple sclerosis - fishing for the surrogate. Eur J Neurol. 17: 344-345. 10.1111/j.1468-1331.2009.02893.x.
Schroecksnadel K, Zangerle R, Bellmann-Weiler R, Garimorth K, Weiss G, Fuchs D: Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection. Curr Drug Metab. 2007, 8: 225-236. 10.2174/138920007780362608.
Fredrikson S, Link H, Eneroth P: CSF neopterin as marker of disease activity in multiple sclerosis. Acta Neurol Scand. 1987, 75: 352-355. 10.1111/j.1600-0404.1987.tb05458.x.
Ott M, Demisch L, Engelhardt W, Fischer PA: Interleukin-2, soluble interleukin-2-receptor, neopterin, L-tryptophan and beta 2-microglobulin levels in CSF and serum of patients with relapsing-remitting or chronic-progressive multiple sclerosis. J Neurol. 1993, 241: 108-114. 10.1007/BF00869773.
Sucher R, Schroecksnadel K, Weiss G, Margreiter R, Fuchs D, Brandacher G: Neopterin, a prognostic marker in human malignancies. Cancer Lett. 287: 13-22. 10.1016/j.canlet.2009.05.008.
Murr C, Widner B, Wirleitner B, Fuchs D: Neopterin as a marker for immune system activation. Curr Drug Metab. 2002, 3: 175-187. 10.2174/1389200024605082.
Wandinger KP, Sturzebecher CS, Bielekova B, Detore G, Rosenwald A, Staudt LM, McFarland HF, Martin R: Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes. Ann Neurol. 2001, 50: 349-357. 10.1002/ana.1096.
Boylan MT, Crockard AD, Duddy ME, Armstrong MA, McMillan SA, Hawkins SA: Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation. Immunol Lett. 2001, 75: 191-197. 10.1016/S0165-2478(00)00310-2.
Polman C, Kappos L, White R, Dahlke F, Beckmann K, Pozzilli C, Thompson A, Petkau J, Miller D: Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology. 2003, 60: 37-43.
Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri L, Sala A, Capobianco M, Bertolotto A: Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology. 2008, 70: 1119-1127. 10.1212/01.wnl.0000304040.29080.7b.
Cook SD, Quinless JR, Jotkowitz A, Beaton P: Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients. Neurology. 2001, 57: 1080-1084.
Gilli F, Bertolotto A, Sala A, Hoffmann F, Capobianco M, Malucchi S, Glass T, Kappos L, Lindberg RL, Leppert D: Neutralizing antibodies against IFN-beta in multiple sclerosis: antagonization of IFN-beta mediated suppression of MMPs. Brain. 2004, 127: 259-268. 10.1093/brain/awh028.
Gilli F, Marnetto F, Caldano M, Sala A, Malucchi S, Capobianco M, Bertolotto A: Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1. Mult Scler. 2006, 12: 47-57. 10.1191/135248506ms1245oa.