Glatiramer acetate (Copaxone) therapy induces CD8+ T cell responses in patients with multiple sclerosis
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
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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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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GA-specific CD8+ T cell responses are differentially upregulated followi...
GA-specific CD8+ T cell responses are differentially upregulated following GA therapy. CFSE-based proliferation assays were performed on longitudinal PBMC specimens obtained from five MS patients on daily GA therapy. (a) GA-specific proliferative responses from a representative patient (no. MS1) are shown at the pretreatment time point and at 3, 7, 11, and 15 months after the initiation of GA therapy. The data represent gated CD4+/CD8– or CD8+/CD4– T cells. CFSE staining is shown on the x axis and CD4 staining on the y axis. The gray populations represent nondividing cells. The numbers next to the darker populations represent the proliferating fraction of CD4+ and CD8+ T cells. The mean background proliferation ranged from 0.29 to 4.36 in various experiments. (b) This graph represents longitudinal mean ΔPF values (± 2 SEM) of CD4+ and CD8+ T cell responses to GA, MBP, and TT from all five MS patients on GA therapy (Table 1). The pretreatment time point (0) and the 3-, 7-, and 11-month time points are shown. *Statistically significant increase of GA-specific CD8+ T cell responses, compared with those in the pretreatment specimens (P < 0.05).