Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate

Aktaş, Orhan; Ari, Neziha Senem; Rieks, M.; Hoffmann, Volker; Schimrigk, Sebastian; Przuntek, H.; Pöhlau, Dieter

doi:10.1034/j.1600-0404.2001.00125.x

Cited by 11 publications

(8 citation statements)

References 28 publications

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“…In two reports [1,13] evidence of a modulation in peripheral T-cell apoptosis during treatment with GA has been also provided. Aktas and colleagues [1] showed that T-cells apoptosis, after in vitro stimulation with GA, declined under the baseline and was equal in treated patients and controls.…”

Section: Discussionmentioning

confidence: 94%

“…Aktas and colleagues [1] showed that T-cells apoptosis, after in vitro stimulation with GA, declined under the baseline and was equal in treated patients and controls. Hence the authors demonstrate a general involvement of GA in the compensation of altered apoptosis in T helper cells.…”

Section: Discussionmentioning

confidence: 97%

“…Glatiramer acetate (GA) has also been shown to modulate in vitro apoptosis susceptibility of T-helper lymphocytes [1] and to induce [13] a significant enhancement of the apoptosis rate in CD4+ T cells. However, the GA effects on the different mechanisms of apoptosis had never been investigated until the present work.…”

Section: Introductionmentioning

confidence: 99%

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Glatiramer acetate induces pro–apoptotic mechanisms involving Bcl–2, Bax and Cyt–c in peripheral lymphocytes from multiple sclerosis patients

et al. 2005

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Apoptotic deletion of autoreactive T-cells is defective in patients with multiple sclerosis (MS). Glatiramer acetate (GA) treatment seems to restore apoptosis of detrimental T-cells. We analyzed the mitochondria membrane pro- (Bax) and anti-apoptotic (Bcl- 2) and cytosolic pro-apoptotic (Cyt-c, APAF-1) proteins expression in peripheral lymphocytes from relapsing-remitting (RR) MS patients during GA treatment. Blood samples were collected from 8 healthy controls (HCs) and from 8 RR MS patients prior to and every three months during the 9 months of GA treatment. Peripheral blood mononuclear cells (PBMNCs) Bcl-2, Bax, Cyt-c and APAF-1 were quantified by western blot followed by densitometric scanning and Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl-2 ratios were calculated. T-cells were in vitro tested for oxygen consumption by a respirometric analysis. Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl-2 ratios in untreated MS patients were significantly (p < 0.05) lower than in HCs. Bax/Bcl-2 ratio increased (p = 0.03) and Cyt-c/Bcl-2 ratio showed a trend to increase during the 9 months of GA treatment in MS patients. A reduction of 58% and 59% in oxygen consumption by PBMNCs was evident after GA treatment in vitro or when GA treated patients' cells were compared with those from HCs, respectively. Our findings suggest that GA exerts a regulatory effect on peripheral T lymphocytes through pro-apoptosis mechanisms involving mitochondria and cytosolic proteins.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

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Glatiramer acetate induces pro–apoptotic mechanisms involving Bcl–2, Bax and Cyt–c in peripheral lymphocytes from multiple sclerosis patients

et al. 2005

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“…To study apoptosis sensitivity isolated PBMC were cultured either without any stimuli or with PHA plus IL-2 and spontaneous cell death or anti-CD95 mAbmediated cell death was measured [25][26][27][28]38]. When apoptosis sensitivity of PBMC from MS patients was compared to healthy controls a small relative resistance of MS-PBMC was found [25][26][27] or was even not detectable [28,38].Yet, such studies do not reflect that autoreactive T cells might only represent a small minority within a mixture of mononuclear cells which could exhibit a different apoptosis phenotype. Our findings clearly show that a small subpopulation such as T reg can exhibit just the opposite phenotype regarding spontaneous and inducible apoptosis in comparison to the majority of T cells mixed with.…”

Section: Discussionmentioning

confidence: 99%

Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals

Fritzsching

Korporal

Haas

et al. 2006

Journal of the Neurological Sciences

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“…In previous experiments, we assessed the in vitro apoptosis susceptibility of CD4+ T cells and found that untreated MS patients showed an impaired apoptosis compared with healthy individuals [22]. Interestingly, subsequent therapy of these patients with GA led to a compensation of the observed in vitro differences, indicating that GA therapy might involve the modulation of apoptosis pathways.…”

Section: Introductionmentioning

confidence: 99%

Induction of Apoptosis of CD4+ T Cells by Immunomodulatory Therapy of Multiple Sclerosis with Glatiramer Acetate

Rieks

Hoffmann²,

Aktaş³

et al. 2003

Eur Neurol

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Glatiramer acetate (GA), a mixture of synthetic polypeptides, has beneficial effects on the clinical course and the MRI-defined disease activity of patients with multiple sclerosis (MS). In MS, evidence has been provided that the apoptosis of disease-relevant T cells is dysregulated. In this study, we investigated the effect of GA on T cell apoptosis, T cell activation, and cytokine profile of lymphocytes derived from 19 relapsing-remitting MS patients during the first year of GA therapy. Analysis of blood samples obtained every 6 weeks showed an increase in apoptotic T helper cells after 30 weeks of therapy. This effect remained until the end of the study and was accompanied by an increase in activated T cells and interleukin-4-producing lymphocytes. Thus, in addition to the established effect of GA on the cytokine network, GA-mediated immunomodulation might involve the apoptotic elimination of T helper cells.

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Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate

Abstract: Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.

Cited by 11 publications

References 28 publications

Glatiramer acetate induces pro–apoptotic mechanisms involving Bcl–2, Bax and Cyt–c in peripheral lymphocytes from multiple sclerosis patients

Glatiramer acetate induces pro–apoptotic mechanisms involving Bcl–2, Bax and Cyt–c in peripheral lymphocytes from multiple sclerosis patients

Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals

Induction of Apoptosis of CD4+ T Cells by Immunomodulatory Therapy of Multiple Sclerosis with Glatiramer Acetate

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