Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients

Farina, Cinthia; Vargas, Vivian; Heydari, Narges; Kümpfel, Tania; Meinl, Edgar; Hohlfeld, Reinhard

doi:10.1016/s0165-5728(01)00490-8

Cited by 58 publications

(40 citation statements)

References 10 publications

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“…Additionally, it has been demonstrated that GA may act to cause a switch in the B cell phenotype of patients with MS, leading to the development of low but significant titres of GA-reactive IgG4 antibodies [38]. Because the isotype switch to IgG4 in B cells requires IL-4, an important anti-inflammatory cytokine, this finding further supports the anti-inflammatory action of GA in treated patients.…”

Section: Mechanism Of Actionmentioning

confidence: 70%

The heritage of glatiramer acetate and its use in multiple sclerosis

Comı

Amato

Bertolotto

et al. 2016

Mult Scler Demyelinating Disord

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Multiple sclerosis (MS) is a chronic and progressively debilitating disease of the central nervous system. Treatment of MS involves disease-modifying therapies (DMTs) to reduce the incidence of relapses and prevent disease progression. Glatiramer acetate (Copaxone®) was the first of the currently approved DMTs to be tested in human subjects, and it is still considered a standard choice for first-line treatment. The mechanism of action of glatiramer acetate appears to be relatively complex and has not been completely elucidated, but it is likely that it involves both immunomodulating and neuroprotective properties. The efficacy of glatiramer acetate 20 mg/mL once daily as first-line treatment in relapsingremitting MS is well established, with ample evidence of efficacy from both placebo-controlled and active-comparator controlled clinical trials as well as real-world studies. There is also a considerable body of evidence indicating that the efficacy of glatiramer acetate is maintained in the long term. Clinical trial and real-world data have also consistently shown glatiramer acetate to be safe and well tolerated. Notably, glatiramer acetate has a good safety profile in women planning a pregnancy, and is not associated with foetal toxicity. Until recently, glatiramer acetate was only approved as 20 mg/mL once daily, but a new formulation with less frequent administration, 40 mg/mL three times weekly, has been developed and is now approved in many countries, including Italy. This review examines the mechanism of action, clinical efficacy, safety and tolerability of glatiramer acetate to provide suggestions for optimizing the use of this drug in the current MS therapeutic scenario.

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Section: Mechanism Of Actionmentioning

confidence: 70%

The heritage of glatiramer acetate and its use in multiple sclerosis

Comı

Amato

Bertolotto

et al. 2016

Mult Scler Demyelinating Disord

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“…45 Just as individuals who are naive to GA treatment sometimes have pre-existing (naive) GA reactive T cells, 28 some untreated MS patients reveal an unprimed humoral response against GA, mainly of an IgM, IgG1, and IgG2 isotype. 46 GA-treated MS patients also produce IgG1 and IgG2 anti-GA antibodies, but in contrast to unexposed individuals, GA-treated MS patients frequently develop high titers of IgG4 antibodies against GA. 46 Preferential secretion of IgG4 antibodies might occur secondary to the induction of GA-reactive Th2 cells, as isotype switching to IgG4 is regulated by the Th2 cytokine IL-4. To date, it is considered controversial whether antibodies against GA are of clinical relevance.…”

Section: Cd25mentioning

confidence: 98%

Mechanism of Action of Glatiramer Acetate in Treatment of Multiple Sclerosis

2007

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Summary:Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4 ϩ T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4 FoxP3ϩ regulatory Tcells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.

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“…The T and B cell responses to GA treatment can be monitored with enzyme-linked immunospot (104) and ELISA (105,106), respectively. In a pilot study involving a small number of MS patients, the immunological response to GA correlated well with the treatment response (107).…”

Section: Ga (Copolymer 1 Copaxone)mentioning

confidence: 99%

Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines

Hohlfeld

Wekerle

2004

Proc. Natl. Acad. Sci. U.S.A.

223

133

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Autoimmune T and B cell responses to CNS antigen(s) are thought to drive the pathogenesis of multiple sclerosis (MS), and thus are logical targets for therapy. Indeed, several immunomodulatory agents, including IFN-␤1b, IFN-␤1a, glatiramer acetate, and mitoxantrone, have had beneficial clinical effects in different forms of MS. However, because the available treatments are only partially effective, MS therapy needs to be further improved. Selective (antigen-specific) immunotherapies are especially appealing because in theory they combine maximal efficacy with minimal side effects. Indeed, several innovative immunotherapies have been successfully applied in experimental autoimmune encephalomyelitis. For example, autoreactive T cells can be selectively targeted by means of antigen, T cell receptor, or activation markers. However, experimental autoimmune encephalomyelitis is far from being a perfect approximation of MS because MS is more heterogeneous and the target antigen(s) is (are) not known. Further advances in MS therapy will depend on our growing understanding of the pathogenesis of this still incurable disease.

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Treatment with glatiramer acetate induces specific IgG4 antibodies in multiple sclerosis patients

Cited by 58 publications

References 10 publications

The heritage of glatiramer acetate and its use in multiple sclerosis

The heritage of glatiramer acetate and its use in multiple sclerosis

Mechanism of Action of Glatiramer Acetate in Treatment of Multiple Sclerosis

Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines

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