PMID- 11113226
OWN - NLM
STAT- MEDLINE
DCOM- 20010111
LR  - 20190514
IS  - 0028-3878 (Print)
IS  - 0028-3878 (Linking)
VI  - 55
IP  - 11
DP  - 2000 Dec 12
TI  - Mechanisms of immunomodulation by glatiramer acetate.
PG  - 1704-14
AB  - OBJECTIVE: To define the mechanism of action of glatiramer acetate (GA; formerly 
      known as copolymer-1) as an immunomodulatory treatment for MS. BACKGROUND: The 
      proposed mechanisms of action of GA include 1) functional inhibition of 
      myelin-reactive T cells by human leukocyte antigen (HLA) blocking, 2) T-cell 
      receptor (TCR) antagonism, and 3) induction of T helper 2 (Th2) immunomodulatory 
      cells. In this report, the authors examined the effects of GA on the functional 
      activation of human T-cell clones (TCC) specific for myelin basic protein (MBP) 
      and for foreign antigens. Several questions were addressed: Is the inhibitory 
      effect of GA specific for autoantigens? Is it mediated by blocking the 
      interaction between peptide and HLA molecule? Is GA a partial agonist or TCR 
      antagonist, or does it induce anergy? Does it induce Th2 modulatory T cells? 
      METHODS: The effects of GA on antigen-induced activation of human TCC specific 
      for MBP, influenza virus hemagglutinin, and Borrelia burgdorferi were studied by 
      proliferation and cytokine measurements, TCR downmodulation, and anergy assays. 
      GA-specific TCC were generated in vitro from the peripheral blood of patients and 
      healthy controls by limiting dilution. RESULTS: GA more strongly inhibited the 
      proliferation of MBP, as compared with foreign antigen-specific TCC; in some 
      MBP-specific TCC, the production of Th1-type cytokines was preferentially 
      inhibited. In addition to HLA competition, the induction of anergy, but not 
      direct TCR antagonism, was observed. Numerous GA-specific TCC were generated from 
      the peripheral blood of both MS patients and normal controls, and a fraction of 
      these showed a Th2 phenotype. CONCLUSIONS: This study confirms a preferential 
      inhibitory effect of GA on autoreactive TCC. With respect to cellular mechanisms, 
      although HLA competition appears to play the most important role in functional 
      inhibition in vitro, a direct effect on the TCR may be involved at least in some 
      autoreactive T cells as shown by anergy induction. Although not confirmed at the 
      clonal level, it is demonstrated further that GA induces T cells that crossreact 
      with myelin proteins. GA-specific, Th2-modulatory cells may play an important 
      role in mediating the effect of the drug in vivo.
FAU - Gran, B
AU  - Gran B
AD  - Cellular Immunology Section, Neuroimmunology Branch, NINDS, NIH, Bethesda, MD 
      20892, USA.
FAU - Tranquill, L R
AU  - Tranquill LR
FAU - Chen, M
AU  - Chen M
FAU - Bielekova, B
AU  - Bielekova B
FAU - Zhou, W
AU  - Zhou W
FAU - Dhib-Jalbut, S
AU  - Dhib-Jalbut S
FAU - Martin, R
AU  - Martin R
LA  - eng
GR  - K24 NS02082-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neurology
JT  - Neurology
JID - 0401060
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Peptides)
RN  - 5M691HL4BO (Glatiramer Acetate)
SB  - IM
MH  - Adjuvants, Immunologic/*metabolism
MH  - Flow Cytometry
MH  - Glatiramer Acetate
MH  - Humans
MH  - Major Histocompatibility Complex/immunology
MH  - Multiple Sclerosis/blood/*immunology
MH  - Peptides/blood/*immunology
MH  - T-Lymphocytes/immunology
EDAT- 2000/12/13 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/12/13 11:00
PHST- 2000/12/13 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/12/13 11:00 [entrez]
AID - 10.1212/wnl.55.11.1704 [doi]
PST - ppublish
SO  - Neurology. 2000 Dec 12;55(11):1704-14. doi: 10.1212/wnl.55.11.1704.