Antibody-mediated remyelination operates through mechanism independent of immunomodulation

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Abstract

A set of antibodies capable of binding glial cells promotes remyelination in models of multiple sclerosis (MS). Within this set, the mouse antibody, SCH94.03, was immunomodulatory implying that immune system mobilization might be integral to remyelination. We evaluated whether the human remyelination-promoting antibody rHIgM22 influences acquired immunity. The antibody did not bind to immune cells, or influence humoral immune responses, antigen presentation, T cell proliferation or cytokine production. Treatment with rHIgM22 had no effect on demyelination or virus infection in two disease models. These results demonstrate that the remyelination-promoting activity of antibody rHIgM22 is not dependent on immunomodulation.

Introduction

Several human and mouse monoclonal IgM antibodies bind to CNS glial cells, promoting CNS remyelination in viral and toxic murine models of multiple sclerosis (MS) Miller et al., 1994, Asakura et al., 1996, Asakura et al., 1998, Warrington et al., 2000, Pavelko et al., 1998, Bieber et al., 2002. Our view is that these antibodies bind to surface determinants expressed by oligodendrocytes, inducing intracellular signals that promote remyelinating activity in situ (Soldan et al., 2003).

The prototypic remyelination-promoting antibody, SCH94.03, also bound dendritic cells in peripheral lymphoid organs and exhibited immunomodulatory effects in vivo (Miller et al., 1996). Systemic treatment with SCH94.03 reduced the number of T cells infiltrating the CNS of SJL/J mice infected with TMEV, increased virus antigen expression without a significant increase in viral RNA or virus titers and suppressed the humoral immune response. Moreover, treatment with SCH94.03 antibody was clinically and histopathologically beneficial in an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE) (Miller et al., 1997). These results demonstrate that remyelinating antibodies can have pleiotropic effects in vivo, with the possibility of unintended consequences. Therefore, it would be useful to identify antibodies exhibiting remyelination-promoting activity in the absence of immunomodulatory activity.

We have now examined a second antibody that promotes remyelination for immunomodulatory properties. The human monoclonal IgM, rHIgM22, was chosen because we have an unlimited source of recombinant antibody produced in vitro (Mitsunaga et al., 2002). This antibody is the best characterized of our human antibodies and the one most likely to be used in human clinical trials. rHIgM22 is originally derived from the serum of a patient with Waldenstrom's macroglobulinemia (Ciric et al., 2001). It binds to human and rodent glial cells in vitro, induces intracellular signals, drives RNA and protein synthesis, and promotes remyelination in viral and toxic models of MS Warrington et al., 2000, Soldan et al., 2003, Bieber et al., 2002.

Here, we evaluated whether rHIgM22 antibody, like its murine counterpart 94.03, modulates the immune system in a number of in vitro and in vivo systems. In a series of analyses, no immunomodulation was observed. We conclude from these studies that the ability of an antibody to promote remyelination can be separated from its ability to modulate the immune response.

Section snippets

Isolation of rHIgM22, sHIgM39 and sHIgM47

The rHIgM22 antibody was isolated from culture supernatant by precipitation with polyethyleneglycol 6000 (Fluka). The precipitate was dissolved in PBS, clarified by centrifugation and dialyzed against water overnight. The resultant precipitate was dissolved in PBS, clarified by centrifugation and enriched on a Superose-6 column (Amersham-Pharmacia).

Isotype control antibodies sHIgM39 and sHIgM47 were isolated from patients with monoclonal gammopathies. The antibody was concentrated by dialysis

The human antibody rHIgM22 induces myelin repair in the spinal cord of demyelinated mice and directly stimulates calcium response in mixed glial cultures in vitro

We have previously shown that the antibody sHIgM22 and its recombinant form, rHIgM22, induce remyelination in mouse models of demyelinating disease (Mitsunaga et al., 2002). An example of remyelinated spinal cord induced by rHIgM12 is shown in Fig. 1. An important common biological activity of IgM antibodies with demonstrable ability to promote myelin repair, including rHIgM22, is the induction of calcium flux in cultured glial cells (Soldan et al., 2003). The structural integrity and

Discussion

We have postulated three general mechanisms that mediate antibody-induced CNS remyelination Bieber et al., 2001, Warrington et al., 2001. The rHIgM22 binds glial cells and directly induces intracellular changes in cell function, possibly driving remyelination events in vivo. A second remyelination-promoting activity could be antibody enhanced opsonization of myelin debris in the lesions, facilitating its removal by phagocytic cells. Once a lesion is cleared of debris, the process of spontaneous

Acknowledgments

We thank Mr. and Mrs. E. Applebaum for their generous support. This work was supported by NIH grant RO1-NS24180 and Acorda Therapeutics.

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