Clinical response to glatiramer acetate correlates with modulation of IFN-γ and IL-4 expression in multiple sclerosis

Abstract

Objective To determine whether glatiramer acetate (GA)-induced lymphoproliferation and IFN-γ and IL-4 modulation correlate with the clinical response in multiple sclerosis (MS).

Background GA therapy involves the induction of anti-inflammatory cytokine shifts. However, it is not known whether this response correlates with the clinical outcome.

Methods Thirty-six relapsing-remitting (RR) MS patients were treated with GA for at least two years, and classified clinically as GA-responders (GA-R=22) or hypo/non-responders (GA-HR/NR = 14). Proliferation of peripheral blood mononuclear cells (PBMC) to GA and Tetanus toxoid (TT), as well as IL-4 and IFN-γ ELISPOT, were performed.

Findings There was no difference in PBMC proliferation to GA or TT between GA-R and GA-HR/NR before and during treatment (P>0.05). The mean number of IFN-γ ELISPOTS in unstimulated, TT and anti-CD3/CD28-stimulated PBMC was lower among GA-R (unstimulated: GA-R =10.1±6.21 (n=22) versus GA-HR/NR=17.8±12.7 (n=14), P=0.04; TT-GA-R =12.2±4.06 (n=12) versus GA-HR/NR=26.8±21.0 (n=8), P=0.028; anti-CD-3/CD28 GA-R=217.3±140.4 (n=22) versus GA-HR/NR=368.5±170.1 (n=14), P=0.006). In contrast, the number of IL-4 ELISPOTS remained unchanged in the GA-R group, but was progressively reduced in the GA-HR/NR group during GA therapy (GA-HR/NR IL-4: pre-Rx: 59±34 versus 22±11 at 12 months (n =6), P=0.0429). The IL-4/ IFN-γ ratio in anti-CD3/CD28-stimulated PBMC was significantly higher among GA-R compared to GA-HR/NR (P=0.0474).

Interpretation Lymphoproliferation to GA did not differentiate GA-R from GA-HR/NR. However, reduced IFN-γ expression and stable IL-4 expression in anti-CD3/CD28-stimulated PBMC, and an increased IL-4/IFN-γ ratio was associated with favorable clinical response. More data are needed to validate the prospective use of IL-4/IFN-γ expression in PBMC as a biomarker of clinical response to GA for individual patients. Multiple Sclerosis 2007; 13: 754-762. http://msj.sagepub.com

Keywords

multiple sclerosis glatiramer acetate interferon-gamma Interleukin-4

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References

Fridkis-Hareli M. , Aharoni R. , Teitelbaum D. , Arnon R. , Sela M. , Strominger JL Binding ofl random copolymers ofl three amino acids to class II MHC molecules . Int Immunol 1999; 11: 635-41 .

Fridkis-Hareli M. , Neveu JM , Robinson RA , Lane WS , Gauthier L. , Wucherpfennig KW et al. Binding motifls ofl copolymer 1 to multiple sclerosis and rheumatoid arthritis-associated HLA-DR molecules . J Immunol 1999; 162: 4697-704 .

Fridkis-Hareli M. , Rosloniec EF , Fugger L. , Strominger JL Synthetic amino acid copolymers that bind to HLA-DR proteins and inhibit type II collagen-reactive T cell clones . Proc Natl Acad Sci USA 1998; 95: 12528-31 .

Fridkis Hareli M. , Santabrogio L. , Stern JN , Fugger L. , Brosnan C. , Strominger JL Novel synthetic amino acid copolymers that inhibit autoanitigen-specific T cell responses and suppresses EAE . J Clin Invest 2002; 109: 1635-43 .

Fridkis-Hareli M. , Stern JN , Fugger L. , Strominger JL Synthetic peptides that inhibit binding ofl myelin basic protein 85-89 epitope to MS associated HLA-DR2 molecules and MBP-specific T cell responses . Hum Immunol 2001; 62: 753-63 .

Aharoni R. , Teitelbaum D. , Sela M. , Arnon R. Bystander suppression ofl experimental autoimmune encephalomyelitis by T-cell lines and clones ofl the Th2 type induced by copolymer 1 . J Neuroimmunol 1998; 91: 1358 .

Aharoni R. , Teitalbaum D. , Sela M. , Amon R. Copolymer 1 induces T cells ofl the T-helper type 2 that cross-react with myelin basic protein and suppress experimental autoimmune encephalomyelitis . Proc Natl Acad Sci USA 1997; 94: 10821 .

Arnon R. The development ofl Cop 1 (Copaxone), an innovative drug flor the treatment ofl multiple sclerosis: personal reflections . Immunol Lett 1996; 50: 1-15 .

Aharoni R. , Teitelbaum D. , Leitner O. , Meshorer A. , Sela M. , Arnon R. Specific Th2 cells accumulate in the central nervous system ofl mice protected against experimental autoimmune encephalomyelitis by copolymer-1 . Proc Natl Acad Sci USA 2000; 97: 11472-77 .

10.

Dhib-Jalbut SS Glatiramer acetate (Copaxone) therapy flor multiple sclerosis . Pharmacol Therapeut 2003 ; 245-55 .

11.

Gran B. , Tranquill LR , Chen M. , Bielekova B. , Zhou W. , Dhib-Jalbut SS et al. Mechanisms ofl immunomodulation by glatiramer acetate . Neurology 2000; 55: 170414 .

12.

Johnson KP , Brooks BR , Cohen JA , Ford C. , Goldstein J. , Lisak RR et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results ofl phase III multicenter, double-blind, placebo-controlled trial . Neurology 1995; 45: 105 .

13.

Miller AS , Shapiro R. , Gershtein A. , Kinarty H. , Rawashdeh S. , Honigman S. et al. Treatment ofl multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms ofl Th1 to Th2/Th3 immune deviation . J Neuroimmunol 1998; 92: 113-21 .

14.

Qin Y. , Zhang DQ , Prat A. , Pouly S. , Antel J. Characterization ofl T-cell lines derived flrom glatiramer acetate-treated multiple sclerosis patients . J Neuroimmunol 2000; 108: 201-206 .

15.

Comi G. , Filippi M. , Wolinsky JS European/Canadian multicenter, double-blind, randomized, placebo-controlled study ofl the eflflects ofl glatiramer acetate on magnetic resonance imaging - measured disease activity and burden in patients with relapsing multiple sclerosis . Ann Neurol 2001; 49: 290-97 .

16.

Chen M. , Valenzuela RM , Dhib-Jalbut SS Glatiramer acetate-reactive T-cells produce brain-derived neurotrophic flactor . J Neurol Sci 2003; 215: 37-44 .

17.

Dhib-Jalbut SS , Zhan M. , Johnson KP , Martin R. Glatiramer acetate reactive blood mononuclear cells respond to myelin antigens with a Th-2 biased phenotype . J Neuroimmunol 2003; 140: 163-71 .

18.

Chen M. , Gran B. , Costello K. , Johnson KP , Martin R. , Dhib-Jalbut SS Glatiramer acetate induces a Th-2 biased response and crossreactivity with myelin basic protein in patients with MS . Mult Scler 2001; 7: 209-19 .

19.

Chen M. , Johnson KP , Martin R. , Dhib-Jalbut SS Sustained immunological eflflects ofl glatiramer acetate in patients with multiple sclerosis treated flor over 6 years . J Neurol Sci 2002; 15: 71 .

20.

Farina C. , Bergh FT , Albrecht H. , Meinl E. , Yassouridis A. , Neuhaus O. et al. Treatment ofl Copaxone (COP) ELISPOT assay detects COP-induced IL-4 and IFN-g response in blood cells . Brain 2001; 124: 705-19 .

21.

Vieira PL , Heystek HC , Wormmeester J. , Wierenga EA , Kapsenberg ML Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation ofl dendritic cells . J Immunol 2003; 170: 4483 .

22.

Wiesemann E. , Klatt J. , Wenzel C. , Heidenreich F. , Windhagen A. Correlation ofl serum IL-13 and IL-5 levels with clinical response to glatiramer acetate in patients with multiple sclerosis . Clin Exp Neurol 2003; 133: 454 .

23.

Ragheb S. , Abramczyk S. , Lisak D. , Lisak R. Long term therapy with glatiramer acetate in multiple sclerosis: eflflect on T cells . Mult Scler 2001; 7: 43-47 .

24.

Duda PW , Schmied MC , Cook SL , Krieger JI , Hafler DA Galtiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis . J Clin Invest 2000; 105: 967-76 .

25.

Chabot S. , Young FP , Le DM , Metz LM , Myles T. , Yong VW Cytokine production in T lymphocytes- microglia interaction is attenuated by glatiramer acetate: a mechanism flor therapeutic eflficacy in multiple sclerosis . Mult Scler 2002; 8: 299 .

26.

Jansson A. , Ernerudh J. , Kvarnstrom M. , Ekerfelt C. , Vrethem M. Elispot assay detection ofl cytokine secretion in multiple sclerosis patients treated with interfleronbeta1a or glatiramer acetate compared with untreated patients . Mult Scler 2003; 9: 440-45 .

27.

Losy J. , Michalowska-Wender G. , Wender M. Interleukin 12 and interleukin 10 are aflflected diflflerentially by treatment ofl multiple sclerosis with glatiramer acetate (copaxone) . Folia Neuropathol 2002; 40: 173-75 .

28.

Neuhaus O. , Farina C. , Yassouridis A. , Wiendel H. , Then Bergh F. , Dose T. et al. Multiple sclerosis: comparison ofl copolymer-1-reactive T-cell lines flrom treated and untreated subjects reveals cytokine shiflt flrom T-helper 1 to T-helper 2 cells . Proc Natl Acad Sci USA 2000; 97: 7452-57 .

29.

Farina C. , Wagenpfeil S. , Hohfeld R. Immunological assay flor assessing the eflficacy ofl glatiramer acetate (Copaxone) in multiple sclerosis . J Neurol 2002; 249: 1587-92 .

30.

Hong J. , Ningli L. , Xuejun Z. , Biao Z. , Jingwu Z. Induction ofl CD4+ CD25+ regulatory T cells by copolymer-I through activation ofl transcription flactor Foxp3 . PNAS 2005 ; 102: 6449-54 .

31.

Weder C. , Baltariu GM , Wyler KA , Gober HJ , Lienert C. , Schulep M. et al. Clinical and immune responses correlate in glatiramer acetate therapy in multiple sclerosis . Eur J Neurol 2005; 12: 869-78 .