title: Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis.
abstract: Glatiramer acetate (GA; Copaxone) is a random copolymer of glutamic acid, lysine, alanine, and tyrosine that is used therapeutically in patients with multiple sclerosis (MS). To investigate the mechanism of the drug's immunomodulatory effect, we used immunophenotypic approaches to characterize the precise nature of GA-induced T cell responses. We demonstrate here that healthy individuals and untreated MS patients exhibit prominent T cell proliferative responses to GA. However, these responses are different in distinct subsets of T cells. Whereas GA-induced CD4(+) T cell responses are comparable in healthy individuals and MS patients, CD8(+) T cell responses are significantly lower in untreated MS patients. Treatment with GA results in upregulation of these CD8(+) responses with restoration to levels observed in healthy individuals. Both CD4(+) and CD8(+) GA-specific responses are HLA-restricted. GA therapy also induces a change in the cytokine profile of GA-specific CD4(+) and CD8(+) T cells. This study provides the first direct immunophenotypic evidence, to our knowledge, of GA-specific CD8(+) T cell responses and their upregulation during the course of therapy, which may suggest a role for these responses in the immunomodulatory effects of the drug.
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9072, USA. nitin@pathology.swmed.edu
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
authors.forename: Michael P
authors.initials: MP
authors.lastname: Crawford
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan
authors.forename: Robert B
authors.initials: RB
authors.lastname: Ratts
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: David R
authors.initials: DR
authors.lastname: Ambrozak
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.forename: Peter
authors.initials: P
authors.lastname: Stastny
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D000068717:Glatiramer Acetate; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D013936:Thymidine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D010455:Peptides; D000068717:Glatiramer Acetate; D013936:Thymidine