Normal human immunoglobulin suppresses experimental myasthenia gravis in SCID mice

Vassilev, Tchavdar; Yamamoto, Maria Sayu; Aissaoui, Abderrahim; Bonnin, Emmanuelle; Berrih‐Aknin, Sonia; Kazatchkine, Michel D.; Kaveri, Srini V.

doi:10.1002/(sici)1521-4141(199908)29:08<2436::aid-immu2436>3.3.co;2-0

Cited by 10 publications

(12 citation statements)

References 22 publications

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“…The very same preparation of polyclonal human IgM used in this study has been demonstrated to neutralize autoantibodies (28) and alter cytokine expression in experimental autoimmune encephalomyelitis (44) and to be beneficial in a mouse model of myasthenia gravis (45). Polyclonal human IgM, but not IVIg, binds to myelinated tracts in unfixed slices of rodent brain.…”

Section: Discussionmentioning

confidence: 90%

Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis

Warrington

Asakura

Bieber

et al. 2000

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

237

204

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Promoting remyelination, a major goal of an effective treatment for demyelinating diseases, has the potential to protect vulnerable axons, increase conduction velocity, and improve neurologic deficits. Strategies to promote remyelination have focused on transplanting oligodendrocytes (OLs) or recruiting endogenous myelinating cells with trophic factors. Ig-based therapies, routinely used to treat a variety of neurological and autoimmune diseases, underlie our approach to enhance remyelination. We isolated two human mAbs directed against OL surface antigens that promoted significant remyelination in a virusmediated model of multiple sclerosis. Four additional OL-binding human mAbs did not promote remyelination. Both human mAbs were as effective as human i.v. Ig, a treatment shown to have efficacy in multiple sclerosis, and bound to the surface of human OLs suggesting a direct effect of the mAbs on the cells responsible for myelination. Alternatively, targeting human mAbs to areas of central nervous system (CNS) pathology may facilitate the opsonization of myelin debris, allowing repair to proceed. Human mAbs were isolated from the sera of individuals with a form of monoclonal gammopathy. These individuals carry a high level of monoclonal protein in their blood without detriment, lending support to the belief that administration of these mAbs as a therapy would be safe. Our results are (i) consistent with the hypothesis that CNS-reactive mAbs, part of the normal Ig repertoire in humans, may help repair and protect the CNS from pathogenic immune injury, and (ii) further challenge the premise that Abs that bind OLs are necessarily pathogenic. E nhancement of remyelination and protection from axonal injury are important therapeutic goals in the treatment of inflammatory demyelinating central nervous system (CNS) disorders such as multiple sclerosis (MS). Remyelination in MS plaques can occur, but is limited (1, 2) even though oligodendrocyte (OL) progenitors are present in the adult (3, 4). A number of therapeutic strategies to promote remyelination have been tested in experimental animals. Transplantation of OLs (5) or their progenitors (6) into demyelinated tissue produces new myelin. Transplanted OL progenitors also can remyelinate demyelinated lesions in the adult CNS (7) and migrate toward an area of damage when placed in close proximity to the lesion (8). Unresolved issues remain concerning the survival of transplanted OL progenitors in the intact adult CNS and their ability to target to areas of myelin pathology (9). However, if CNS lesions are surgically approachable and axons are still intact, transplantation of glial cells may be a viable therapy for improving functional performance (10).The in vitro administration of growth or trophic factors induces the expansion of OL progenitors (11, 12) or promotes mature OLs to dedifferentiate and subsequently reinitiate a program of myelination (13,14). The in vivo administration of trophic factors via genetically engineered fibroblasts to the injured CNS promotes ax...

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Section: Discussionmentioning

confidence: 90%

Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis

Warrington

Asakura

Bieber

et al. 2000

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

237

204

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“…In contrast, the activation-induced cytidine deaminase-deficient MRL-lpr mice that lack IgG but have increased autoreactive IgM do not develop lupus nephritis (29). There are also reports that administration of IgM has beneficial effects in some experimental autoimmune models (30,31). By analyzing a lupus patient's sera against a multiplex autoantigen microarray, Mohan and colleagues (32) have found that the presence of IgM polyreactivity is correlated with reduced disease severity.…”

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confidence: 99%

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

Mannoor

Matejuk

et al. 2012

The Journal of Immunology

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Natural autoantibodies (NAA) and their associated B cells constitute a substantial proportion of the normal Ab and B cell repertoire. They often have weak reactivity toward a variety of self-Ags such as DNA, nucleoproteins, and phospholipids. It remains controversial whether NAA contribute to or protect from autoimmune diseases. Using site-directed transgenic (sd-tg) mice expressing a prototypic NAA, we investigated the effect of NAA and NAA-producing B cells in disease development in the autoimmune-prone MRL/MpJ-Faslpr (MRL-lpr) mice. We found that the expression of NAA in MRL-lpr mice prevented proteinuria and reduced kidney immune complex formation. The mice had significantly improved survival. Administration of the IgM NAA to MRL-lpr mice also delayed the onset of nephritis. The sd-tg MRL-lpr mice had decreased levels of anti-dsDNA Abs, anti-Hep2 nuclear Abs, and anti-Sm/ribonucleoprotein Abs. There is a shift in the IgG subclass profile from IgG2a and IgG3 to IgG1 in the sd-tg MRL-lpr mice. The CD4+ T cells from the sd-tg MRL-lpr mice had increased expression of the negative costimulatory molecule CTLA-4 and increased production of IL-10 as compared with those from the wild-type mice. Furthermore, the NAA B cells produced large amounts of IL-10 upon TLR stimulation. These results indicate that NAA and NAA-producing B cells play an important role in protection from lupus nephritis and suggest that the NAA B cells may have an immune regulatory function via the provision of IL-10.

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“…Reduced antibody responses to the autoantigen have been reported in other experimental autoimmune diseases in which effective IVIG treatment has been demonstrated, such as experimental autoimmune myositis, experimental autoimmune myocarditis, 10,11 and an experimental murine model of systemic lupus erythematosus 13 . There has also been a report showing that pretreatment by IVIGM reduced serum anti‐AChR antibodies in myasthenic SCID mice reconstituted with thymic cells from a myasthenia gravis patient 19 …”

Section: Resultsmentioning

confidence: 88%

“…IVIG has been employed to treat MG for about two decades 14–17 and was shown to be effective in MG on a long‐term basis without significant side effects 18 . In a SCID mouse model of human MG it has been demonstrated that pretreatment with IVIG and intravenous IgM (IVIGM) decreased the production of anti‐AChR antibodies in the serum and led to a decreased loss of endplate AChR in the diaphragms of treated mice 19 …”

Section: Introductionmentioning

confidence: 99%

Suppression of Experimental Autoimmune Myasthenia Gravis by Intravenous Immunoglobulin and Isolation of a Disease‐Specific IgG Fraction

Fuchs

Feferman

Zhu

et al. 2007

Annals of the New York Academy of Sciences

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Intravenous immunoglobulin (IVIG) administration has been beneficially used for the treatment of a variety of autoimmune diseases including myasthenia gravis (MG). We have demonstrated that IVIG administration in experimental autoimmune MG (EAMG) results in suppression of disease that is accompanied by decreased Th1 cell and B cell proliferation. Chromatography of pooled human immunoglobulins (IVIGs) on immobilized IgG, isolated from rats with EAMG, results in a complete depletion of the suppressive activity of the IVIG. Moreover, the eluate from this EAMG-specific antibody column retains the immunosuppressive activity of IVIG. This study supports the notion that the therapeutic effect of IVIGs is mediated by an antigen-specific anti-immunoglobulin (anti-idiotypic) activity that is essential for its suppressive activity.

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Normal human immunoglobulin suppresses experimental myasthenia gravis in SCID mice

Cited by 10 publications

References 22 publications

Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis

Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

Suppression of Experimental Autoimmune Myasthenia Gravis by Intravenous Immunoglobulin and Isolation of a Disease‐Specific IgG Fraction

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