Glatiramer acetate (Copaxone) therapy induces CD8+ T cell responses in patients with multiple sclerosis
Nitin J. Karandikar, … , Richard A. Koup, Michael K. Racke
Nitin J. Karandikar, … , Richard A. Koup, Michael K. Racke
Published March 1, 2002
Citation Information: J Clin Invest. 2002;109(5):641-649. https://doi.org/10.1172/JCI14380.
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Article Immunology

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

Nitin J. Karandikar, Michael P. Crawford, Xiao Yan, Robert B. Ratts, Jason M. Brenchley, David R. Ambrozak, Amy E. Lovett-Racke, Elliot M. Frohman, Peter Stastny, Daniel C. Douek, Richard A. Koup, Michael K. Racke

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Figure 1

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Untreated MS patients have a deficient CD8+ T cell response to GA. CFSE-...
Untreated MS patients have a deficient CD8+ T cell response to GA. CFSE-based proliferation assays were performed on PBMC specimens from 9 healthy individuals and 23 MS patients. (a) Representative responses from one healthy individual and one RRMS patient are shown. The data represent gated CD3+ T cells, further gated for CD4+/CD8– or CD8+/CD4– T cells. CFSE staining is shown on the x axis and CD8 staining on the y axis (CD8– populations represent gated CD4+ T cells). The gray populations represent nondividing cells. The numbers next to the darker populations represent the proliferating fraction of CD4+ T cells and CD8+ T cells. ΔPF is the difference between specific proliferation and the background (no antigen). Thus, the healthy control had a GA-specific ΔPF of 45.84% for the CD4+ T cells and 29.43% for the CD8+ T cells. The RRMS patient had a CD4+ ΔPF of 35.97% and 3.05% for the CD8+ response. The mean ΔPF was calculated from duplicate cultures in every experiment. (b) The graphs represent mean ΔPF (+ 2 SEM) of GA-specific CD4+ (left panel) and CD8+ (right panel) responses from 9 healthy individuals and 23 untreated MS patients (12 RRMS, 6 PPMS, and 5 SPMS). The responses from the MS patients were compared to those from the healthy individuals. The P values are indicated above the corresponding bars. *Significant differences (P < 0.05).