Polyclonal IgM influence oligodendrocyte precursor cells in mixed glial cell cultures: implications for remyelination

Polyclonal immunoglobulins for intravenous use (IVIg) are a potent immunomodulator and have been shown to be effective in several immune-mediated diseases. This includes inflammatory demyelinating diseases of the central nervous system (CNS) like multiple sclerosis (MS). Besides their immunomodulatory function, IVIg have been proposed to enhance remyelination based on studies in the animal model of Theiler's murine encephalomyelitis virus (TMEV). Disappointingly, recent treatment trials in patients with MS have failed to demonstrate repair of longstanding deficits. Since the clinical trials have used IVIg that contained nearly exclusively IgG, whereas the most pronounced effect in TMEV was seen with IgM, this could be a possible explanation for the negative outcome in the MS trials. Here we have examined the effects of a new polyclonal IgM preparation (IVIgM) on cultured oligodendrocyte precursor cells (OPCs). To achieve successful remyelination, OPCs proliferate, migrate, and differentiate into mature myelinating oligodendrocytes. IVIgM and commercial IVIg preparations had no influence on proliferation and differentiation of either isolated OPCs or OPCs in coculture with microglia. In contrast, IVIgM inhibited the proliferation of OPCs in mixed glial cultures containing astrocytes and microglia. This was not seen in cultures treated with IVIg, albumin, or interferon-gamma (IFN-gamma), suggesting that this is a specific effect of IVIgM. Differentiation was slightly delayed by IVIgM in mixed glial cultures, but this was not statistically significant and interferon-gamma had a similar effect. These results underline the importance of IgM in influencing OPCs and corroborate the in vivo findings that polyclonal IgM are more potent than IgG in their capacity to influence remyelination. The exact mechanism of how this modulation of OPCs is achieved remains unknown, but a complex interaction among all cells present in the CNS has to be postulated.