Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein.

Abstract

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and has been proposed as a candidate drug for multiple sclerosis. Cop 1 is immunologically cross reactive with myelin basic protein (BP) and was shown to inhibit murine BP-specific T-cell lines of various H-2 restrictions. In the present study these findings were extended to include human T-cell lines. Cop 1 competitively inhibited the proliferative responses and interleukin 2 secretion of six BP-specific T-cell lines and 13 clones with several DR restrictions and epitope specificities. Conversely, BP inhibited--albeit to a lesser extent--the response of all the Cop 1-specific T-cell lines and clones, irrespective of their DR restrictions. Another random copolymer of tyrosine, glutamic acid, and alanine, denoted TGA, had no effect on these lines. Neither Cop 1 nor BP inhibited the response of lines and clones specific for purified protein derivative. Cop 1 and BP exerted their cross-inhibitory effects only in the presence of antigen-presenting cells. These results suggest that Cop 1 can compete with BP for the binding to human major histocompatibility complex molecules. In view of recent studies implicating BP reactivity in multiple sclerosis, these findings suggest a possible mechanism for the beneficial effect of Cop 1 in this disease.

Glatiramer Acetate (Copolymer-1, Copaxone) Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells

“…31). With respect to the binding of GA to immune cells, in vitro experiments have shown that GA binds promiscuously to class II MHC (32)(33)(34), thereby competing with MBP-derived peptides for the MBP-specific TCR (35)(36)(37). This is an implausible setting in vivo.…”

“…GA has been shown to bind promiscuously to class II MHC molecules in vitro (32)(33)(34), thus competing with MBP-derived peptides for the MBP-specific TCR (35)(36)(37). Interestingly, GA induces a Th1 to Th2 shift accompanied by the production of the anti-inflammatory cytokine IL-10 both in vitro and in vivo (34, 38 -44).…”

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

“…Although its mechanism of action is not completely known, its inhibition of central nervous system myelin antigens by competing as an MHC ligand may be of importance (20)(21)(22). The ability to stimulate proliferation of Th2 over Th1 cells, suppressing T-cell activity is also of relevance as well (23).…”

Human and Murine CD4 T Cell Reactivity to a Complex Antigen: Recognition of the Synthetic Random Polypeptide Glatiramer Acetate

“…These findings suggest that a random polymer of amino acids with common MHC and TCR contact residues containing frequent spacer, nonbulky amino acids might act as a universal peptide Ag, engaging the TCR in such a manner that the proliferation of many T cells are induced. In this regard, T cell lines and clones with reactivity to GA in vitro have been generated from rats, mice, and other animal species primarily on immunization of the animals with the Ag (10). Interestingly, in retrospect a study using PBMCs from healthy control subjects showed a strong proliferative and IFN-␥ response to GA (22).…”