Mechanisms of immunomodulation by glatiramer acetate

Objective: To define the mechanism of action of glatiramer acetate (GA; for merly known as copolymer-1) as an immunomodulatory treatment for MS. Backgr ound: The proposed mechanisms of action of GA include 1) functional inhibit ion 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) im munomodulatory cells. In this report, the authors examined the effects of G A on the functional activation of human T-cell clones (TCC) specific for my elin basic protein (MBP) and for foreign antigens. Several questions were a ddressed: Is the inhibitory effect of GA specific for autoantigens? Is it m ediated by blocking the interaction between peptide and HLA molecule? Is GA a partial agonist or TCR antagonist, or does it induce anergy? Does it ind uce Th2 modulatory T cells? Methods: The effects of GA on antigen-induced a ctivation of human TCC specific for MBP, influenza virus hemagglutinin, and Borrelia burgdorferi were studied by proliferation and cytokine measuremen ts, TCR downmodulation, and anergy assays. GA-specific TCC were generated i n vitro from the peripheral blood of patients and healthy controls by limit ing dilution. Results: GA more strongly inhibited the proliferation of MBP, as compared with foreign antigen-specific TCC; in some MBP-specific TCC, t he production of Th1-type cytokines was preferentially inhibited. In additi on to HLA competition, the induction of anergy, but not direct TCR antagoni sm, was observed. Numerous GA-specific TCC were generated from the peripher al blood of both MS patients and normal controls, and a fraction of these s howed a Th2 phenotype. Conclusions: This study confirms a preferential inhi bitory effect of GA on autoreactive TCC. With respect to cellular mechanism s, although HLA competition appears to play the most important role in func tional inhibition in vitro, a direct effect on the TCR may be involved at l east in some autoreactive T cells as shown by anergy induction. Although no t 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 viv o.