Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: A randomized, double-blind, placebo-controlled trial

Achiron, Anat; Kishner, Irena; Sarova-Pinhàs, I; Raz, H; Faibel, Meir; Stern, Yael; Lavie, Mor; Gurevich, Michael; Dolev, Mark; Magalashvili, David; Barak, Yoram

doi:10.1016/j.ajo.2004.12.093

Cited by 35 publications

(48 citation statements)

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“…19,20 Extended observation observed a trend for the delayed progression of the disease in the IVIG treated patients as seen from the change in the EDSS scores. However, these preliminary results need to be confirmed prospectively in a larger number of patients.…”

Section: Edss Evaluation During the Clinical Coursementioning

confidence: 99%

Neurodegenerative central nervous system disease as late sequelae of Langerhans cell histiocytosis. Report from the Japan LCH Study Group

Imashuku¹,

Shibata²,

Kobayashi³

et al. 2008

Haematologica

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Clinical features, brain magnetic resonance imaging findings and EDSS scores of 11 patients with neurodegenerative central nervous system Langerhans cell histiocytosis were analyzed in Japan. All patients initially had multi-system-type Langerhans cell histiocytosis; 8 at 1-2 years of age and 3 at a later age. Neurodegenerative central nervous system largermans cell histiocytosis disease developed after a median time interval of 3.9 years from initial diagnosis. With a median follow-up of 4.5 years, 6 patients showed progression of disease with an EDSS score >3. This study demonstrates the importance of early detection of neurodegenerative central nervous system Langerhans cell histiocytosis by brain magnetic resonance imaging, particularly in the follow-up of patients who developed multi-system-type Langerhans cell histiocytosis in early infancy.Key words: Langerhans cell histiocytosis, late sequelae, neurodegenerative central nervous system disease Imashuku S, Shioda Y, Kobayashi R, Hosoi G, Fujino H, Seto S, Wakita H, Oka A, Okazaki N, Fujita N, Minato T, Koike K, Tsunematsu Y, Morimoto A, and the Japan LCH Study Group (JLSG). Neurodegenerative central nervous system disease as late sequelae of Langerhans cell histiocytosis. Report from the Japan LCH Study Group. Haematologica 2008; 93(4):615-618.

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Section: Edss Evaluation During the Clinical Coursementioning

confidence: 99%

Neurodegenerative central nervous system disease as late sequelae of Langerhans cell histiocytosis. Report from the Japan LCH Study Group

Imashuku¹,

Shibata²,

Kobayashi³

et al. 2008

Haematologica

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“…Many of these effects are deduced based on animal models of Ab-mediated autoimmunity and ex vivo studies (10). However, therapeutic benefit of IVIg is also clearly established in several T cell-mediated autoimmune pathologies (11)(12)(13)(14). Previous reports from our laboratory show that the beneficial effect of IVIg in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis and a T cell-mediated pathology, is associated with a peripheral expansion of CD4 + CD25 +…”

mentioning

confidence: 99%

Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

Othy

Hegde

Topçu

et al. 2013

The Journal of Immunology

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Despite an increasing use of high-dose therapy of i.v. gammaglobulin (IVIg) in the treatment of various T cell– and Ab-mediated inflammatory and autoimmune diseases, comprehension of the mechanisms underlying its therapeutic benefit has remained a major challenge. Particularly, the effect of IVIg in T cell–mediated autoimmune conditions remains unexplored. Using an actively induced experimental autoimmune encephalomyelitis model, a T cell–mediated autoimmune condition, we demonstrate that IVIg inhibits the differentiation of naive CD4 T cells into encephalitogenic subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3+ regulatory T cells. Further, IVIg renders effector T cells less pathogenic by decreasing the expression of encephalitogenic molecular players like GM-CSF and podoplanin. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB is dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Additionally, F(ab′)2 fragments also retained this function of IVIg. IVIg or F(ab′)2 fragments decrease the sphingosine-1 phosphate receptor on CD4 cells, thus sequestering these cells in the draining lymph nodes and decreasing their infiltration into the CNS. Our study reveals a novel role of Igs in the modulation of polarization and trafficking of T lymphocytes, accounting for the observed beneficial effect in IVIg therapy.

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“…This is an important observation that further validates IVIg testing in suitable subsets of early onset MS. 28 Indeed, the cumulative probability of developing clinically definite MS was significantly lower in IVIg-treated persons presenting with first neurologic event in a randomized, double-blind, placebocontrolled trial. 29 Previous studies have shown that IVIg can modulate diverse lymphoid and myeloid cell populations. 30,31 Thus, at therapeutic concentrations used in autoimmune diseases (0.15 mM), IVIg induces a downmodulation of monocyte-derived DC, which in turn fail to support T-cell proliferation.…”

mentioning

confidence: 99%

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

Ephrem

Chamat

Miquel

et al. 2008

Blood

254

217

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The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fc␥ receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the devel- IntroductionNatural CD4 ϩ CD25 ϩ regulatory T cells (nTreg) expressing the lineage marker Foxp3 are the key players in controlling immune responses and in maintenance of T-cell homeostasis. 1,2 Therapeutic induction of the Treg represents a novel approach in the treatment of autoimmune pathology. 3,4 CD4 ϩ CD25 ϩ Foxp3 ϩ nTreg develop in thymus, in contrast to "adaptive" or "induced" Treg that develop in peripheral lymphoid tissues from CD4 ϩ conventional T cells (Tconv) and are frequently Foxp3 Ϫ . Although studies have highlighted the role of cytokines interleukin-2 (IL-2), transforming growth factor-␤ (TGF-␤), and IL-10 in Treg development, other factors or mechanisms crucial to Treg homeostasis are not elucidated. 5 Intravenous immunoglobulin (IVIg) is an established therapy for several immune disorders. [6][7][8][9] Several mutually nonexclusive mechanisms have been proposed to explain the beneficial effect of IVIg 7,8 ; however, the issue remains debated and an ongoing challenge. For instance, the Fc␥R-mediated effects of IVIg 10-12 cannot entirely account for its proven benefit in several peripheral and central demyelinating diseases such as GuillainBarré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and relapsing-remitting multiple sclerosis (MS), which are primarily mediated by autoreactive T cells. 6,7,13,14 Because the T cells do not express Fc␥R, 15 the observed effects raise certain speculations, that is, if these effects could be attributed to a direct interaction of the variable region of the immunoglobulin (Ig) G molecules with the T cell or an indirect influence via other cell types such as dendritic cells (DC).During the induction phase of experimental autoimmune encephalomyelitis (EAE), myelin reactive proinflammatory CD4 ϩ T cells proliferate in the periphery, infiltrate the central nervous system (CNS) during the effector phase and, in concert with other inflammatory mediators, lead to demyelination characterized by a progressive paralysis. 16 Natural remission and recovery from relapse in EAE is associated with the recruitment or generation of Treg in the CNS. 17,18 We and others have shown that IVIg protects against EAE development only when administered prophylactically. 14,19 We reasoned that IVIg manifests its protective effect in EAE through an early modulation of autoreactive T cells, and therefore we investigated the regulatory mechanisms, particularly the effect of IVIg on regulatory T cells. Methods Animals, antigen, and tissue culture mediumWe purchased C57BL/6J mice (females, 6-8 weeks of age) from Charles River Laboratories (L'Arbresle, F...

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Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: A randomized, double-blind, placebo-controlled trial

Cited by 35 publications

References 20 publications

Neurodegenerative central nervous system disease as late sequelae of Langerhans cell histiocytosis. Report from the Japan LCH Study Group

Neurodegenerative central nervous system disease as late sequelae of Langerhans cell histiocytosis. Report from the Japan LCH Study Group

Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

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