Copaxone Abstracts

  1. Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin {alpha}M{beta}2
    J Immunol 2008 Mar 15;180(6):3946-56

  2. Short-term combination of Glatiramer Acetate with IV steroid treatment preceding treatment with GA alone assessed by MRI-disease activity in patients with Relapsing/Remitting Multiple Sclerosis
    J Neurol Sci 2008 Mar 15;266(1-2):44-50

  3. Longitudinal Magnetic Resonance Spectroscopic imaging of Primary/Progressive Multiple Sclerosis patients treated with Glatiramer Acetate: multicenter study
    Mult Scler 2008 Jan;14(1):73-80

  4. Production of Brain-Derived NeurotTrophic Factor by MonoNuclear Cells of patients with Multiple Sclerosis treated with Glatiramer Acetate, Interferon-beta-1a, and high doses of ImmunoGlobulins
    Mult Scler 2007 Apr;13(3):313-31

  5. NeuroGenesis and NeuroProtection in the CNS - fundamental elements in the effect of Glatiramer Acetate on treatment of Autoimmune Neurological Disorders
    Mol NeuroBiol 2007 Dec;36(3):245-53

  6. Cognitive function in Relapsing Multiple Sclerosis: Minimal changes in a 10-year clinical trial
    J Neurol Sci 2007 Apr 15;255(1-2):57-63

  7. Randomized, double-blind, dose-comparison study of Glatiramer Acetate in Relapsing-Remitting MS
    Neurology 2007 Mar 20;68(12):939-44

  8. Glatiramer Acetate in Primary/Progressive Multiple Sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial
    Ann Neurol 2007 Jan;61(1):14-24

  9. Glatiramer Acetate reduces Lymphocyte proliferation and enhances IL-5 and IL-13 production through modulation of Monocyte-derived Dendritic Cells in Multiple Sclerosis
    Clin Exp Immunol 2006 Feb;143(2):357-62

  10. Mechanism of action of Glatiramer Acetate in Multiple Sclerosis and its potential for the development of new applications
    Proc Natl Acad Sci USA 2004 Sep 15

  11. Type 2 Monocyte and Microglia differentiation mediated by Glatiramer Acetate therapy in patients with Multiple Sclerosis
    J Immunol 2004 Jun 1;172(11):7144-53

  12. AntiBody-mediated ReMyelination operates through mechanism independent of ImmunoModulation
    J NeuroImmunol 2004 Jan;146(1-2):153-61

  13. Mechanisms of action of Interferons and Glatiramer Acetate in Multiple Sclerosis
    Neurology 2002 Apr 23;58(8 Suppl 4):S3-9

  14. Multiple Sclerosis: Modulation of Apoptosis susceptibility by Glatiramer Acetate
    Acta Neurol Scand 2001 Nov;104(5):266-270

  15. Synthetic peptides that inhibit binding of the Myelin Basic Protein 85-99 Epitope to Multiple Sclerosis-associated HLA-DR2 molecules and MBP-specific T-Cell responses
    Hum Immunol 2001 Aug;62(8):753-63

  16. Humoral and Cellular Immune responses to Copolymer-1 in Multiple Sclerosis patients treated with Copaxone(R)
    J NeuroImmunol 2001 Apr 2;115(1-2):152-60

  17. United States open-label Glatiramer Acetate extension trial for Relapsing Multiple Sclerosis: MRI and clinical correlates
    Mult Scler 2001 Feb;7(1):33-41

  18. Multiple Sclerosis: Comparison of Copolymer-1- Reactive T-Cell lines from treated and untreated subjects reveals Cytokine shift from T-Helper 1 to T-Helper 2 cells
    Proc Natl Acad Sci USA 2000 Jun 20;97(13):7452-7457

  1. Meta-Analysis of clinical trials with Copolymer-1 in MS
    Eur Neurol 2000 May;43(4):189-193

  2. Glatiramer Acetate (Copaxone) treatment in Relapsing/Remitting MS: quantitative MR assessment
    Neurology 2000 Feb 22;54(4):813-7

  3. Glatiramer Acetate (Copaxone) induces degenerate, Th2-polarized Immune responses in Multiple Sclerosis
    J Clin Invest 2000 Apr;105(7):967-76

  4. Multiple Sclerosis: comparison of Copolymer-1- reactive T-Cell lines from treated and untreated subjects reveals Cytokine shift from T-Helper 1 to T-Helper 2 cells
    Proc Natl Acad Sci USA 2000 Jun 20;97(13):7452-7

  5. Specific Th2 cells accumulate in the Central Nervous System of mice protected against Experimental AutoImmune EncephaloMyelitis by Copolymer-1
    Proc Natl Acad Sci USA 2000 Oct 10;97(21):11472-7

  6. Sustained clinical benefits of Glatiramer Acetate in Relapsing Multiple Sclerosis patients observed for 6 years. Copolymer-1 Multiple Sclerosis Study Group
    Mult Scler 2000 Aug;6(4):255-66

  7. Characterization of T-Cell lines derived from Glatiramer-Acetate-treated Multiple Sclerosis patients
    J NeuroImmunol 2000 Aug 1;108(1-2):201-6

  8. T-Cell immunity to Copolymer-1 confers NeuroProtection on the damaged Optic Nerve: possible therapy for optic neuropathies
    Proc Natl Acad Sci USA 2000 Jun 20;97(13):7446-51

  9. Effects of Glatiramer Acetate on MRI - measured disease activity and burden in Relapsing Multiple Sclerosis
    Ann Neurol 2001 Mar;49(3):290-7

  10. Treatment of Multiple Sclerosis with Copaxone (COP): Elispot assay detects COP-induced InterLeukin-4 and Interferon-gamma response in blood cells
    Brain 2001 Apr;124(Pt 4):705-719

  11. Glatiramer Acetate inhibition of Tumor Necrosis Factor-alpha-induced RANTES expression and release from U-251 MG human Astrocytic cells
    J NeuroChem 2001 Jun;77(5):1208-17

  12. Increase in Serum levels of Uric Acid, an endogenous AntiOxidant, under treatment with Glatiramer Acetate for Multiple Sclerosis
    Mult Scler 2000 Dec;6(6):378-81

  13. HLA-DRB1*1501 and response to Copolymer-1 therapy in Relapsing/Remitting Multiple Sclerosis
    Neurology 2001 Dec 11;57(11):1976-9

  14. Polyreactive AntiBodies to Glatiramer Acetate promote Myelin repair in murine model of DeMyelinating Disease
    FASEB J 2002 Aug 1;16(10):1260-1262

  15. Clinical course after change of ImmunoModulating Therapy in Relapsing/Remitting Multiple Sclerosis
    Eur J Neurol 2006 May;13(5):471-4


Meta-Analysis Of Clinical Trials With Copolymer-1 In Multiple Sclerosis

La Mantia L, Milanese C, D'Amico R
Eur Neurol 2000 May;43(4):189-193
National Institute of Neurology C. Besta, Institute of Pharmacological Research M. Negri, Dept of Neurology, Milan, Italy
PMID# 1082864

Glatiramer Acetate (Copolymer-1) was licensed in the USA in 1996 for the treatment of Relapsing/Remitting Multiple Sclerosis.

In order to assess its efficacy, a meta-analysis of all randomized controlled trials was performed. Two double-blind studies, accounting for a total number of 299 patients, contribute to this analysis.

Patients undergoing the treatment have decreased probability of relapse at 12 months (OR 0.17, 95% CI 0.05-0.51, p = 0.002) and of unsustained progression of Disability at 24 and 35 months (OR 0.57, 95% CI 0.34-0.95, p = 0.031, and OR 0.50, 95% CI 0.28-0.90, p = 0.019).

These data suggest that Glatiramer Acetate represents an alternative to Interferon treatment in Relapsing/Remitting Multiple Sclerosis. However, further evidence of efficacy is required to justify its use in clinical practice.

Copyright 2000 S. Karger AG, Basel


Glatiramer Acetate (Copaxone) Treatment In Relapsing/Remitting MS: Quantitative MR Assessment

Ge Y, Grossman RI, Udupa JK, Fulton J, Constantinescu CS, Gonzales-Scarano F, Babb JS, Mannon LJ, Kolson DL, Cohen JA
Neurology 2000 Feb 22;54(4):813-7
Hospital of the Univ of Pennsylvania, Dept of Radiology, Philadelphia 19104-4283, USA
PMID# 10690968; UI# 20152827

To evaluate the efficacy of Glatiramer Acetate (GA, Copaxone; Teva Pharmaceutical Industries, Ltd., Petah Tiqva, Israel) by MRI-based measures in patients with Relapsing/Remitting (RR) MS.

Twenty-seven patients with Clinically Definite RR-MS were treated with either 20 mg of GA by daily subcutaneous self-injection (n = 14) or placebo (n = 13) for approximately 24 months.

Axial dual-echo fast-Spin-Echo T2-weighted images and T1-weighted images before and after Gadolinium (Gd) were acquired at 1.5 tesla and transferred into an image processing computer system.

The main outcome measures were the number of Gd-enhanced T1 and T2 lesions and their volume as well as Brain Parenchyma volume.

The values of age, disease duration, Expanded Disability Status Scale (EDSS) score, the number of T1- and T2-weighted lesions, and their volume were similar between GA- and placebo-receiving groups at the entry of this study.

There was a decrease in the number of T1-enhanced lesions (p = 0.03) and a significant percent annual decrease of their volume in GA recipients compared with those of placebo recipients.

There were no significant differences between changes in the two groups in the number of T2 Lesions and their volume.

The loss of Brain tissue was significantly smaller in the GA group compared with that of the placebo group.

These results show that GA treatment may decrease both Lesion Inflammation and the rate of Brain Atrophy in RR-MS.


Glatiramer Acetate (Copaxone) Induces Degenerate, Th2-Polarized Immune Responses In Multiple Sclerosis

Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA
J Clin Invest 2000 Apr;105(7):967-76
Brigham and Women's Hospital and Harvard Medical School, Center for Neurologic Diseases, Laboratory of Molecular Immunology, Boston, Massachusetts 02115, USA
PMID# 10749576; UI# 20213446

We examined the effect of Glatiramer Acetate, a random Copolymer of Alanine, Lysine, Glutamic Acid, and Tyrosine, on Antigen-specific T-Cell responses in patients with Multiple Sclerosis (MS).

Glatiramer Acetate (Copaxone) functioned as a universal Antigen, inducing proliferation, independent of any prior exposure to the polymer, in T-Cell lines prepared from MS or healthy subjects.

However, for most patients, daily injections of Glatiramer Acetate abolished this T-Cell response and promoted the secretion of IL-5 and IL-13, which are characteristic of Th2 Cells.

The surviving Glatiramer Acetate-reactive T-Cells exhibited a greater degree of degeneracy as measured by cross-reactive responses to combinatorial Peptide libraries.

Thus, it appears that, in some individuals, in vivo administration of Glatiramer Acetate induces highly cross-reactive T-Cells that secrete Th2 Cytokines.

To our knowledge, Glatiramer Acetate is the first agent that suppresses human AutoImmune Disease and alters Immune function by engaging the T-Cell receptor.

This compound may be useful in a variety of AutoImmune Disorders in which Immune deviation to a Th2 type of response is desirable.


Multiple Sclerosis: Comparison Of Copolymer-1- Reactive T-Cell Lines From Treated And Untreated Subjects Reveals Cytokine Shift From T-Helper 1 To T-Helper 2 Cells

Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, Wekerle H, Hohlfeld R
Proc Natl Acad Sci USA 2000 Jun 20;97(13):7452-7
Max Planck Institute of NeuroBiology, Dept of NeuroImmunology, Am Klopferspitz 18A, 82152 Martinsried, Germany
PMID# 10861011; UI# 20319047

Copolymer-1 (COP), a standardized mixture of synthetic polypeptides consisting of L-Glutamic Acid, L-Lysine, L-Alanine, and L-Tyrosine, has beneficial effects in Multiple Sclerosis and Experimental AutoImmune EncephaloMyelitis.

We selected a panel of 721 COP-reactive T-Cell lines (TCL) from the blood of COP-treated and untreated Multiple Sclerosis patients and from healthy donors by using the split-well cloning technique.

All TCL selected with COP proliferated in response to COP but not to Myelin Basic Protein (MBP). Conversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP.

We used IntraCellular double-immunofluorescence flow cytometry for quantitative analysis of Cytokine production (IL-4, IFN-γ) by the TCL.

The majority of the COP-reactive TCL from untreated Multiple Sclerosis patients and normal donors predominantly produced IFN-γ and, accordingly, were classified as T-Helper 1 cells (Th1).

In contrast, the majority of the COP-reactive TCL from COP-treated patients predominantly (but not exclusively) produced IL-4-i.e., were Th2 (P < 0.05 as assessed by using a suitable preference intensity index).

Longitudinal analyzes revealed that the Cytokine profile of COP-reactive TCL tends to shift from Th1 to Th2 during treatment.

Interestingly, although there was no proliferative cross-reaction, about 10% of the COP-reactive TCL responded to MBP by secretion of small amounts of IL-4 or IFN-γ, depending on the Cytokine profile of the TCL.

These results are consistent with a protective effect of COP-reactive Th2 Cells.

It is hypothesized that these cells are activated by COP in the periphery, migrate into the Central Nervous System, and produce ImmunoModulatory Cytokines after local recognition of MBP.


Specific Th2 Cells Accumulate In The Central Nervous System Of Mice Protected Against Experimental AutoImmune EncephaloMyelitis By Copolymer-1

Aharoni R, Teitelbaum D, Leitner O, Meshorer A, Sela M, Arnon R
Proc Natl Acad Sci USA 2000 Oct 10;97(21):11472-7
The Weizmann Institute of Science, Depts of Immunology and Biological Services, Rehovot 76100, Israel
PMID# 11027347; UI# 20481932

This study addresses the issue of the effect of ImmunoModulating therapies in the target organ, the Central Nervous System (CNS), in the case of Multiple Sclerosis.

Copolymer 1 (Cop 1, Copaxone, Glatiramer Acetate), an approved drug for the treatment of Multiple Sclerosis, is a potent inducer of Th2 Regulatory Cells in both mice and humans.

Highly reactive Cop 1-specific T-Cell lines that secrete IL-4, IL-5, IL-6, IL-10, and Transforming Growth Factor-ß in response to Cop 1 and crossreact with Myelin Basic Protein (MBP) at the level of Th2 Cytokine secretion were established from both Brains and Spinal Cords of Cop 1-treated mice.

In contrast, no reactivity to the control Antigen Lysozyme could be obtained in Lymphocytes isolated from CNS of mice injected with Lysozyme.

Adoptively transferred labeled Cop 1-specific Suppressor Cells were found in Brain sections 7 and 10 days after their injection to the periphery, whereas Lysozyme-specific cells were absent in the CNS.

Hence, Cop 1-induced Th2 cells cross the Blood-Brain Barrier and accumulate in the CNS, where they can be stimulated in situ by MBP and thereby exert therapeutic effects in the diseased organ.

This therapeutic effect was manifested, in Brains of Experimental AutoImmune EncephaloMyelitis-induced mice, by a decrease in the inflammatory Cytokine Interferon-gamma and by secretion of the anti-inflammatory Cytokine IL-10 in response to the AutoAntigen MBP.


Sustained Clinical Benefits Of Glatiramer Acetate In Relapsing Multiple Sclerosis Patients Observed For 6 Years.

Copolymer-1 Multiple Sclerosis Study Group

Johnson KP, Brooks BR, Ford CC, Goodman A, Guarnaccia J, Lisak RP, Myers LW, Panitch HS, Pruitt A, Rose JW, Kachuck N, Wolinsky JS
Mult Scler 2000 Aug;6(4):255-66
Univ of Maryland, Dept of Neurology, Baltimore, Maryland 21201, USA
PMID# 10962546; UI# 20420517

In a randomized, placebo-controlled, double-blind study, Glatiramer Acetate (Copaxone) reduced the relapse rate and slowed accumulation of Disability for patients with Relapsing/Remitting Multiple Sclerosis.

Of the original 251 patients randomized to receive Glatiramer Acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug.

The majority of the original double-blind cohort continues to receive Glatiramer Acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse.

The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg Glatiramer Acetate were well tolerated.

The mean annual relapse rate of the patients who received Glatiramer Acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23.

Of the group who have received Glatiramer Acetate without interruption for 5 or more years, 69.3% were Neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS).

Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out.

This study demonstrates the sustained efficacy of Glatiramer Acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with Relapsing forms of Multiple Sclerosis.


Characterization 0f T-Cell Lines Derived From Glatiramer Acetate-Treated MS Patients

Qin Y, Zhang DQ, Prat A, Pouly S, Antel J
J NeuroImmunol 2000 Aug 1;108(1-2):201-6
Montreal Neurological Institute, NeuroImmunology Unit, McGill University, 3801 Univsity Street, Quebec, H3A 2B4, Montreal, Canada
PMID# 10900354; UI# 20361894

We analyzed the effects of Glatiramer Acetate (GA) therapy on in vitro proliferative responses and Cytokine production by Lymphocytes derived from Multiple Sclerosis patients receiving this therapy.

We confirmed that Lymphocytes derived from GA naive patients show a high frequency of response when initially exposed to GA in vitro; this frequency decreased following GA therapy.

The frequency of Lymphocytes responding to whole MBP stimulation did not change with GA therapy.

GA- and MBP-specific T-Cell lines generated from these patients by repeated cycles of in vitro stimulation did not cross react. Some (23%) whole MBP-reactive T-Cell lines did cross react with MBP peptide 83-99.

The mean levels of Interferon-gamma (IFN-γ) secretion and the mean ratio of IFN-γ/IL-5 were lower for GA-reactive cell lines, derived from patients both prior to and during GA therapy, compared to MBP-reactive T-Cell lines.

The proportion of IFN-γ cells in unfractionated Lymphocyte preparations derived from the GA-treated patients did not differ from that found for healthy controls.

Our findings indicate that GA-reactive T-Cell lines derived from GA-treated MS patients continue to show a relative Th2 Cytokine bias consistent with a bystander suppressor function.

GA treatment is not associated with a Cytokine phenotype shift in the total T-Cell or MBP-reactive T-Cell populations.


T-Cell Immunity To Copolymer-1 Confers NeuroProtection On The Damaged Optic Nerve: Possible Therapy For Optic Neuropathies

Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, Cohen IR, Schwartz M
Proc Natl Acad Sci USA 2000 Jun 20;97(13):7446-51
The Weizmann Institute of Science, Depts of NeuroBiology and Immunology, 76100 Rehovot, Israel
PMID# 10861010; UI# 20319046

We recently reported that the post traumatic spread of degeneration in the damaged Optic Nerve can be attenuated by the adoptive transfer of AutoImmune T-Cells specific to Myelin Basic Protein.

However, it would be desirable to obtain Immune NeuroProtection free of any possible AutoImmune Disease.

In an attempt to obtain disease-free Immune NeuroProtection, we used the synthetic four-Amino Acid polymer Copolymer-1 (Cop-1), which is known not to be EnCephalitoGenic despite its cross-reactivity with Myelin Basic Protein.

We show here that active immunization with Cop-1 administered in adjuvant, as well as adoptive transfer of T-Cells reactive to Cop-1, can inhibit the progression of secondary degeneration after crush injury of the rat Optic Nerve.

These results have implications for the treatment of Optic Neuropathies.


Effects Of Glatiramer Acetate On MRI - Measured Disease Activity And Burden In Relapsing Multiple Sclerosis

European/Canadian multicenter, double-blind, randomized, placebo-controlled study

European/Canadian Glatiramer Acetate Study Group
Comi G, Filippi M, Wolinsky JS
Ann Neurol 2001 Mar;49(3):290-7
Univ of Milan, Dept of NeuroScience, Scientific Institute, Ospedale San Raffaele, Milan, Italy
PMID# 11261502; UI# 21157951

Two prior double-blind, placebo-controlled, randomized trials demonstrated that Glatiramer Acetate (GA) reduces relapse rates in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with Magnetic Resonance Imaging (MRI) in patients with RRMS.

Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection.

Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI.

The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images.

Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of HypoIntense Lesions seen on unenhanced T1-weighted images.

Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables.

Treatment with GA showed a significant reduction in the total number of enhancing Lesions compared with placebo (-10.8, 95% confidence interval -18.0 to -3.7; p = 0.003).

Consistent differences favoring treatment with GA were seen for almost all secondary end points examined:

  1. Number of new enhancing lesions (p < 0.003)
  2. Monthly change in the volume of enhancing lesions (p = 0.01)
  3. Change in volume (p = 0.006)
  4. Number of new lesions seen on T2-weighted images (p < 0.003)

The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer Acetate significantly reduced MRI-measured disease activity and burden.


Treatment Of Multiple Sclerosis With Copaxone (COP): Elispot Assay Detects COP-Induced InterLeukin-4 And Interferon-γ Response In Blood Cells

Farina C, Bergh FT, Albrecht H, Meinl E, Yassouridis A, Neuhaus O, Hohlfeld R
Brain 2001 Apr;124(Pt 4):705-719
Max Planck Institute of NeuroBiology, Dept of NeuroImmunology, Martinsried; Ludwig Maximilians University, Institute for Clinical NeuroImmunology, Dept of Neurology, Klinikum Grosshadern; and Max Planck Institute of Psychiatry, Dept of Statistics, Munich, Marianne-Strauss-Klinik, Berg, Germany
PMID# 11287371

Copolymer-1 (Copaxone or COP) inhibits Experimental Allergic EncephaloMyelitis and has beneficial effects in Multiple Sclerosis. There is presently no practical in vitro assay for monitoring the Immunological effects of COP.

We used an automated, computer-assisted enzyme-linked ImmunoAdsorbent spot assay for detecting COP-induced Interferon-gamma (IFN-γ) and InterLeukin-4 (IL-4) producing cells.

And a standard proliferation assay to assess the Immunological response to COP in Peripheral Blood MonoNuclear Cells from 20 healthy donors, 20 untreated Multiple Sclerosis patients and 20 COP-treated Multiple Sclerosis patients. Compared with untreated and healthy controls,

    COP-treated patients showed:
  1. A significant reduction of COP-induced proliferation
  2. A positive IL-4 Elispot response
      - mediated predominantly by CD4+ Cells, after stimulation with a wide range of COP concentrations
  3. An elevated IFN-γ response
      - partially mediated by CD8+ Cells, after stimulation with high COP concentrations

All three effects were COP-specific as they were not observed with the control Antigens, Tuberculin-purified protein or Tetanus Toxoid.

The COP-induced changes were consistent over time and allowed correct identification of COP-treated and untreated donors in most cases. We propose that these criteria may be helpful to monitor the Immunological response to COP in future clinical trials.


Glatiramer Acetate Inhibition Of Tumor Necrosis Factor-alpha-Induced RANTES Expression And Release From U-251 MG Human Astrocytic Cells

Li QQ, Burt DR, Bever CT
J NeuroChem 2001 Jun;77(5):1208-17
Univ of Maryland School of Medicine, Dpts of Neurology and Pharmacology and Experimental Therapeutics, and USA Medical Research Service, VA Maryland Health Care System, Baltimore, Maryland, USA
PMID# 11389171; UI# 21283067

Glatiramer Acetate is an approved drug for the treatment of Multiple Sclerosis (MS).

RANTES is a beta-family Chemokine that manifests ChemoAttractant activity for T-Lymphocytes and Monocytes/Macrophages implicated in the PathoGenesis of MS Lesions.

However, the effect of Glatiramer Acetate on the regulation of RANTES secretion in Glial Cells is unknown.

In the present study, we demonstrate for the first time that treatment of human U-251 MG Astrocytic Cells with Glatiramer Acetate blocks Tumor Necrosis Factor-alpha (TNF-alpha)-induced RANTES mRNA and protein in a dose- and time-dependent manner.

This effect is attributed to inhibition of transcription and a 40% decrease in transcript stability.

Furthermore, our electrophoretic mobility shift assays of nuclear extracts from TNF-alpha-treated cells, reveal an increase in DNA-binding activity specific for the nuclear factor-kappa B (NF-kappaB) binding site, in the 5'-flanking promoter region of the human RANTES Gene.

And, that this increase in NF-kappaB binding activity is prevented by pretreatment with Glatiramer Acetate or the NF-kappaB inhibitors.

These findings suggest that Glatiramer Acetate may exert its therapeutic effect in MS partially through inhibiting NF-kappaB activation and Chemokine production.


Increase In Serum Levels Of Uric Acid, An Endogenous AntiOxidant, Under Treatment With Glatiramer Acetate For Multiple Sclerosis

Constantinescu CS, Freitag P, Kappos L
Mult Scler 2000 Dec;6(6):378-81
University Hospital, Queen's Medical Centre, Division of Clinical Neurology, Nottingham, UK
PMID# 11212132; UI# 21079636

Free radicals including Peroxynitrite are induced in Multiple Sclerosis (MS). Antioxidant and Peroxynitrite inhibitor Uric Acid (UA), suppresses the MS animal model Experimental AutoImmune Encephalomyelitis (EAE).

MS patients have lower average serum UA than controls. An inverse relationship exists between MS and Gout, Glatiramer Acetate (GA) suppresses EAE and is beneficial in Relapsing MS.

We investigated Serum UA changes during open-label treatment of Relapsing MS with GA. Ten patients (six females, four males, aged 19 to 39 years, mean age 32 years) completed 6 months of GAA (Copaxone 20 mg s.c daily).

Of these, nine completed 12 months. After 6 months on GA, serum UA (normal, 173359 micromol/ml for women, 258-491 micromol/ml for men) increased in nine and marginally decreased (302 to 300 micromol/ml) in a single patient.

Mean UA significantly increased from 240 to 303 micromol/ml (P=0.0014). At 12 months, UA remained significantly higher than at start (P=0.006) decreasing in only one patient.

In contrast, we found no significant UA changes after 6 and 12 months of treatment in 21 MS patients treated with Interferon-ß-1a (Avonex), or in 11 treated with Interferon-ß-1a (Rebif), or in five placebo-treated controls.

Increasing UA, a natural inhibitor of free radicals, may represent a mechanism of action of Glatiramer Acetate in MS.


HLA-DRB1*1501 and response to Copolymer-1 therapy in Relapsing/Remitting Multiple Sclerosis

Fusco C, Andreone V, Coppola G, Luongo V, Guerini F, Pace E, Florio C, Pirozzi G, Lanzillo R, Ferrante P, Vivo P, Mini M, Macri M, Orefice G, Lombardi ML
Neurology 2001 Dec 11;57(11):1976-9
Universita Fedrico II, Servizio Immunoematologia e Trasfusione, Napoli, Italy
PMID# 11739812; UI# 21603061

Copolymer-1 (Cop-1) is a random synthetic Amino Acid copolymer, effective in the treatment of the Relapsing/Remitting form of MS (RRMS).

In vitro and in vivo studies suggest that the mechanism of Cop-1 involves its binding to Major Histocompatibility Complex Class II molecules as an initial step.

To assess a possible relationship between Human Leukocyte Antigen (HLA) Alleles and response to Cop-1 therapy.

Eighty-three patients with RRMS, 44 treated with Cop-1 and 39 with Interferon-beta-1a (IFN-beta-1a) for 2 years, were typed by molecular methods for HLA Class II Genes and subgrouped according to clinical outcome.

Data have shown a possible positive correlation between presence of DRB1*1501 and response to Cop-1 therapy (p = 0.008). No relationship between HLA Alleles and therapy has been found in IFN-beta-1a treated patients.

Results suggest that DRB1*1501 might be relevant for the clinical outcome in Cop-1 treated patients and, if confirmed in larger studies, it could be helpful in the selection of RRMS patients for different therapeutic options.


PolyReactive AntiBodies To Glatiramer Acetate Promote Myelin Repair In Murine Model Of DeMyelinating Disease

Ure DR, Rodriguez M
FASEB J 2002 Aug 1;16(10):1260-1262
Mayo Medical and Graduate School, Departments of, Immunology and, Neurology, Rochester, Minnesota, USA
PMID# 12060672

Using a murine model of DeMyelinating disease, we demonstrate that ReMyelination of Spinal Cord Axons is promoted by AntiBodies to Glatiramer Acetate (GA, Copolymer-1, Copaxone), a therapeutic agent for Multiple Sclerosis (MS).

Glatiramer Acetate is a mixture of randomly synthesized Peptides that induces both T-Cell activation and AntiBody production in all treated individuals.

These observations prompted us to compare the independent effects of adoptively transferred GA-reactive T-Cells and AntiBodies in mice with chronic inflammatory DeMyelination induced by Theiler's Virus.

Transferred T-Cells had no effect on lesion load or the extent of ReMyelination. Purified polyclonal GA AntiBodies also did not alter lesion load, which suggests that neither GA T-Cells or AntiBodies were pathogenic.

On the contrary, GA AntiBodies enhanced the normally low level of ReMyelination in chronic lesions.

The AntiBodies, which were primarily ImmunoGlobulin (Ig) G1 and IgG2, cross-reacted with Oligodendrocytes, PeriVascular infiltrating cells, Astrocytes, and Neurons in Spinal Cord sections.

In Glial cultures they bound subsets of early lineage Oligodendrocytes and Microglia. Thus, several mechanisms may have contributed to the promotion of ReMyelination.

These results support the hypothesis that the AntiBody response in GA-treated patients is beneficial by facilitating repair of DeMyelinated lesions.


Clinical course after change of ImmunoModulating Therapy in Relapsing/Remitting Multiple Sclerosis

Caon C, Din M, Ching W, Tselis A, Lisak R, Khan O
Eur J Neurol 2006 May;13(5):471-4
Wayne State University School of Medicine, Multiple Sclerosis Center, Department of Neurology, Detroit, MI, USA
PMID# 16722971

We examined the clinical course after switching Disease-Modifying Therapy (DMT) in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

Eighty-five consecutive RRMS patients who received weekly Interferon-beta-1a (IFN-beta-1a) 6 MU i.m. for at least 18 months were enrolled.

Baseline annualized relapse rate (ARR) for the 2 years prior to initiating therapy with IFN-beta-1a was obtained from charts.

All 85 patients received treatment with IFN beta-1a at 6 MU i.m. weekly for 18-24 months (mean 19.7 months). Treatment with IFN-beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005).

All 85 patients were then switched to Glatiramer Acetate (GA) 20 mg s.c. daily and prospectively followed up for 36-42 months (mean 37.5 months).

Patients were switched because of persistent clinical disease activity (n=62) or persistently unacceptable toxicity (n=23) as determined by the treating Neurologist.

Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001).

Subgroup analysis showed that in patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001).

In contrast, in patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN-beta-1a to 0.47 on GA (P, non-significant).

Our observations suggest that clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice.

More definitive consensus criteria incorporating Magnetic Resonance Imaging and clinical observations for defining optimal response and tolerability need to be developed for the routine clinical management of RRMS patients receiving DMT.

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