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Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4+CD25+FOXP3+CD31+ T-cells in patients with multiple sclerosis

https://doi.org/10.1016/j.jneuroim.2009.06.011Get rights and content

Abstract

Naturally occurring regulatory T-cells (Treg) exhibit impaired function in patients with relapsing-remitting multiple sclerosis (RRMS) resulting from an age-inappropriate disproportion between prevalences of newly generated CD31-coexpressing naive Treg and long-lived memory Treg in the periphery. Recent evidence suggests that the immunomodulatory action of glatiramer acetate (GA) includes effects on Treg function and frequencies. We prospectively assessed suppressive activities and frequencies of Treg and Treg subsets in 15 patients with RRMS undergoing long-term therapy with GA. Treatment for up to six months reconstituted naive Treg and increased total Treg numbers with concomitant reversion of the Treg defect.

Introduction

Naturally occurring regulatory T-cells of CD4+CD25+FOXP3+ phenotype (Treg) are functionally impaired in patients with relapsing-remitting multiple sclerosis (RRMS) (Viglietta et al., 2004, Haas et al., 2005, Venken et al., 2008). Our own findings demonstrate that the Treg defect detectable in MS is related to an altered homeostasis of circulating Treg as proportions of newly generated naïve CD45RA+CD45ROCD31+ among CD4+CD25+FOXP3+ T-cells (recent thymic emigrant, “RTE”-Treg) in peripheral blood are decreased while memory Treg of CD45RACD45RO+CD31 phenotype are reciprocally expanded thereby keeping total Treg numbers constant (Haas et al., 2007).

Glatiramer acetate (GA, Copaxone®) is an immunomodulatory drug approved for the prophylaxis of clinical and radiologic disease activity in patients with RRMS. The proposed mechanism of GA is its cross-reaction with myelin basic protein and T-cell receptors resulting in interference with myelin-specific immune stimulation and bystander suppression (Yong, 2002, Hartung, 2004). Recent studies suggest that GA may also target numbers and activity of Treg. However, this has not been addressed in a longitudinal study. Here, we collected serial blood specimens from patients undergoing long-term therapy with GA to assess treatment effects on both Treg mediated antiproliferative effects and on the homeostatic composition of Treg subsets. We show that GA by shifting RTE-Treg and total Treg to higher prevalences persistently improves Treg function back to normal levels.

Section snippets

Study subjects

Fifteen patients with RRMS according to MacDonald or Poser criteria (McDonald et al., 2001, Poser et al., 1983; means of age: 37.3 years, previous relapses: 2.2, disease duration: 3.2 years, EDSS: 2.0) and 16 healthy control donors (HC, mean age 33.4 years) were included in the study. Blood specimens were taken before institution of treatment with Copaxone® as well as three and six months thereafter. During the observation period all patients remained clinically stable. The protocol was approved

GA-treatment induces a shift from memory TH and memory Treg towards RTE-TH and RTE-Treg

At baseline, patients with MS harbored reduced proportions of both naive TH and RTE-TH (naive TH: MS 22.6 ± 10.3%, HC 42.1 ± 6.7%; p < 0.001; RTE-TH: MS 16.2 ± 4.9%, HC 29.3 ± 5.7%; p = 0.001), and increased percentages of memory TH (MS 58.1 ± 14.3%, HC 44.8 ± 7.4%; p = 0.02) (Fig. 1A).Total Treg were slightly decreased in numbers in patients versus HC (MS 5.0 ± 1.0%, HC 5.8 ± 2.1%; p = 0.217), contained reduced frequencies of both naive Treg (MS 18.3 ± 4.8%, HC 28.7 ± 12.6%; p = 0.044) and RTE-Treg (MS 4.7 ± 2.2%, HC 8.2 ± 

Discussion

Both inhibitory function and homeostasis of Treg are disturbed in patients with RRMS (Viglietta et al., 2004, Haas et al., 2005, Venken et al., 2008). In this longitudinal study we show that prolonged treatment with GA shifts Treg and conventional CD4+ T-cells towards a more naive phenotype. Within the Treg compartment, the rise in percentages of naive and RTE cells is accompanied by a concomitant decline in memory cells and altogether, results in an increase of total Treg numbers above levels

Acknowledgements

We thank multiple sclerosis patients and healthy donors for the participation in this study. This study was supported in part by a non-restricted grant from TEVA Pharma GmbH, the Gemeinnützige Hertie-Stiftung (1.319.110/01/11 and 1.01.1/04/003), the Young Investigator Award from the Faculty of Medicine, University of Heidelberg (to BF and AS), and by the Competence Network for Multiple Sclerosis funded by the Federal Ministry of Education and Research (FKZ 01GI0905 - 0913). None of the funding

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