Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins (“IVIg”)

Abstract

High-dose intravenous immunoglobulin (IVIg) treatment has become a promising immune therapy that can modulate the immune system at several levels, including the complement cascade. In relation to inflammatory demyelinating disease, there is some clinical evidence for the suppression of disease activity by IVIg, while a role in promoting remyelination after experimental myelin damage has been described. Antibody and complement deposition have been implicated in the immune attack in some cases of multiple sclerosis (MS), and to investigate the mechanisms of action of IVIg, we studied the effect of IVIg using the model of complement-mediated cell injury on oligodendroglia in vitro. There was no effect on direct complement lysis of the oligodendroglial cell line CG4, but antibody-dependent complement damage was inhibited in a dose-dependent manner by IVIg. These results were confirmed with primary cultures of oligodendrocyte precursor cells (OPC) and oligodendrocytes. The addition of excess C1, C3, and C4 did not influence the inhibitory effect of IVIg, implying that binding of these complement components does not play a role, in contrast to other experimental models of complement damage. F(ab′)₂ immunoglobulin fragments were at least partially responsible for the effect. We conclude that IVIg may be protective in antibody-mediated complement injury of oligodendrocytes and their progenitors, and that this effect is likely to be mediated via antibody binding, rather than interference with complement activation. Inhibition of inflammatory mechanisms, as opposed to a direct effect on remyelinating cells, may underlie the role of IVIg in promoting myelin repair in experimental models.

Introduction

During the last decade, treatment with high-dose intravenous immunoglobulins (IVIg) has become an established component in the management of autoimmune-mediated demyelinating diseases (Stangel et al., 1999b). In multiple sclerosis (MS), relatively small trials have shown IVIg to reduce relapse rate and MRI activity (Fazekas et al., 1997; Achiron et al., 1998; Sorensen et al., 1998).

The mechanism of action of IVIg remains obscure (Stangel et al., 1999b). Although some studies suggest an effect on T cell immunity (Pashov et al., 1998), the consensus view is that changes in humoral immune mechanisms are more likely to explain the therapeutic activity. An effect on anti-idiotypic networks is one possibility (Rossi and Kazatchkine, 1989), but interference with the complement system has been clearly demonstrated both in animal models (Basta, 1996) and in patients with dermatomyositis where depositions of C3 and membrane attack complex disappeared following IVIg treatment (Basta and Dalakas, 1994). Antibody-mediated complement injury has also been proposed as a contributory mechanism leading to demyelination in some cases of MS (Storch et al., 1998; Genain et al., 1999).

In virus-induced and toxic animal models of CNS demyelination certain antibodies are also capable of promoting remyelination (Asakura et al., 1998; Pavelko et al., 1998). Several mechanisms have been proposed for this effect, namely direct stimulation of oligodendrocytes, immunomodulation, and opsonization of debris (McGavern et al., 1999). We have shown previously that IVIg has no direct effect on the proliferation, differentiation and migration of cultured oligodendrocyte precursor cells (OPC), the remyelinating cell in the CNS (Stangel et al., 1999a). We therefore explored the potential of IVIg to protect oligodendroglia from complement mediated cytotoxicity as a potential mechanism for explaining the clinical and experimental observations relating to its use.