Etretinate Augments Interferon Beta-1b Effects on Suppressor Cells in Multiple Sclerosis

Qu, Zhi; Pliskin, Neil H.; Jensen, Mark A.; White, David M.; Arnason, Barry G. W.

doi:10.1001/archneur.58.1.87

Cited by 19 publications

(15 citation statements)

References 17 publications

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“…Thus, most studies and, as a consequence, therapeutic strategies are focused on the dynamics of CD4 ϩ T-cell responses. CD8 ϩ T cells have been implicated in the pathogenesis [15][16][17][18][19][20][21][23][24][25]27,28,65,66 as well as regulation [29][30][31][32][33][34][35][36][37][38] of autoimmune demyelination in MS and EAE. However, CNS-specific CD8 ϩ T-cell responses in MS have been largely overlooked or thought to be uncommon.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay

Crawford

Yan

Ortega

et al. 2004

Blood

225

187

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Section: Discussionmentioning

confidence: 99%

“…[26][27][28] CD8 ϩ T cells have also been implicated as regulatory cells in autoimmune demyelination. [29][30][31][32][33][34][35][36][37][38] These reports emphasize the necessity of dissecting and characterizing the prevalence, specificity, and functional role of both CD4 ϩ and CD8 ϩ T cells in these diseases.…”

Section: Introductionmentioning

confidence: 99%

High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay

Crawford

Yan

Ortega

et al. 2004

Blood

225

187

View full text Add to dashboard Cite

“…[50 -52] An enhancing effect of IFN-b on antigen-specific T cell responses has been documented by Pacocha et al [53] On the other hand, IFN-b did also augment suppressor functions of CD8 þ T cells. [11,50,54] Generally, IFN-b treatment seems to induce profound changes of cytokine expression patterns, which are more complex than just lowering the Th1/Th2 ratio. Keeping in mind the methodical and biological limitation of cytokine determinations it is a task of the future to find out, whether long-term therapy over several years with high doses of exogenous IFN-b is changing the physiological balance of pro-and anti-inflammatory cytokines in MS patients.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte Subpopulations, Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

et al. 2003

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At present, the most efficient therapeutical treatment of multiple sclerosis (MS) is achieved by IFN-beta. However, its in vivo effects remain incompletely understood. If applied parenterally, the hydrophobic IFN-beta acts primarily on blood cells with probable selectivity for functionally different lymphocyte subpopulations, monocytes and granulocytes. We have investigated the expression of the activation marker interleukin-2 receptor-alpha (CD25) on CD3+ T cells, CD19+ B cells, foetal-type gamma(delta)+CD3+ T cells and foetal-type CD5+CD19+ B cells of the peripheral blood. In addition, the oxidative burst activity and apoptosis have been determined in mononuclear and polymorphonuclear blood cells, respectively. The study accompanied a phase III trial with IFN-beta1b (BETAFERON, Schering). Two groups of MS patients with relapsing-remitting course of the disease have been investigated at 8 time points (days 0, 5, 15, 31, 60, 90, 180 and 270 after starting therapy): (1) verum group (n = 8) with application of 8 Mill. units IFN-beta1 b every other day, and (2) placebo group (n = 4) with application of placebo for 3 months and therapy as in (1) from day 90 onward. The main results were: (1) Activated T cells decreased until day 180 in the verum group and return thereafter to pre-treatment values, whereas in the placebo group the values remained relatively stable over the whole observation period. (2) Activated B cells increased between days 90 and 270 in both groups, i.e. after verum application in both groups. (3) Foetal-type B cells were more activated than total B and T cells with increase over time in both groups. (4) Foetal-type T cells exerted relatively stable intra-individual levels with generally low CD25 expression, but punctual CD25 peaks in both groups. (5) The spontaneous oxidative burst was higher in lymphocytes, more variable in monocytes and faster increasing in granulocytes in the verum group than in the placebo group. (6) Apoptosis of mononuclear cells and granulocytes showed similar variations in the verum and placebo groups with the exception of a selective increase over time of the proportion of granulocytes undergoing induced apoptosis in the verum group. It is concluded that IFN-beta has the following main effects on the immune system of MS patients: (1) the T cell immunity is systemically and reversibly suppressed, (2) the foetal-type lymphocytes, which are responsible for the first line of defence of infections, are stimulated in the long range, (3) the oxidative burst activity is increased in lymphocytes and granulocytes and instable in monocytes, and (4) the inducibility of apoptosis in granulocytes is increased. Re-examination of the altered blood cell parameters after long-term IFN-beta therapy is warranted.

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“…A regulatory role for CD8 + T cells has been demonstrated in EAE (39)(40)(41)(42). Upregulation of such suppressive ability has also been seen following combined therapy with etretinate and IFN-β1b (43). From these studies, it is tempting to speculate that the diminished CD8 + T cell response to GA in untreated MS patients may be reflective of the global defect of regulatory cells in this subset.…”

Section: Figurementioning

confidence: 95%

Glatiramer acetate (Copaxone) therapy induces CD8+ T cell responses in patients with multiple sclerosis

Karandikar¹,

Crawford²,

Yan³

et al. 2002

J. Clin. Invest.

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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

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Etretinate Augments Interferon Beta-1b Effects on Suppressor Cells in Multiple Sclerosis

Cited by 19 publications

References 17 publications

High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay

High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometric assay

Lymphocyte Subpopulations, Oxidative Burst and Apoptosis in Peripheral Blood Cells of Patients with Multiple Sclerosis–Effect of Interferon-β

Glatiramer acetate (Copaxone) therapy induces CD8+ T cell responses in patients with multiple sclerosis

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