Human and murine CD4 T cell reactivity to a complex antigen: Recognition of the synthetic random polypeptide glatiramer acetate

The capacity of glatiramer acetate (GA), a random copolymer of alanine, lys ine, glutamic acid, and tyrosine to stimulate primary in vitro human and mu rine T cell proliferation was examined. PBMCs isolated from healthy humans and relapsing remitting multiple sclerosis patients and spleen cells from i nbred strains of mice, expressing different H-2 haplotypes, were used as so urces of non-GA-primed lymphocytes. GA functioned as a universal Ag, induci ng dose-dependent proliferation of all non-GA-primed human and murine T cel l populations tested. Moreover, GA stimulated PBMCs derived ex vivo from hu man cord blood, strongly suggesting that GA can activate both naive and mem ory T cells. The human T cell proliferative responses to GA were HLA class II DR-restricted by virtue of the ability of anti-class II Ab to inhibit T call proliferation, and the demonstration that individual GA specific human T cell clones were HLA class II DR-restricted by either restriction elemen t but not both. Furthermore, GA-reactive T cells secreted Th0 cytokines and expressed a diverse repertoire of TCR, Limiting dilution analysis indicate d that the T cell precursor frequency among the healthy human adults tested ranged from 1:5,000 to 1:125,000, Given that all of the T cell populations tested were isolated from non-GA-primed donors, it appears that virtually all humans and murine strains contain significant numbers of T cell populat ions cross-reactive with GA. These findings may explain the recent clinical finding that daily s.c. administration of GA ameliorates the progression o f multiple sclerosis.