Remyelination of cytokine- or antibody-demyelinated CNS aggregate cultures is inhibited by macrophage supplementation

Remyelination in CNS aggregate cultures is determined both by macrophage enrichment and the mode of demyelination. Despite the same degree of myelin loss, accumulation of MBP in anti-MOG antibody-demyelinated aggregates overtakes that of controls, while recovery is significantly delayed following IFN-gamma-induced demyelination. In antibody-treated cultures, remyelination was associated with a significant increase in culture supernatant levels of TGF-beta1, FGF-2, and PDGF-AA as well as an induction of TNF-alpha. immediately following removal of the demyelinating insult. The impaired recovery in IFN-gamma-treated cultures, denoted by a significant reduction in TGF-beta1, was reversed by treatment with hrTGF-beta1. Macrophage supplementation of the cultures prior to the addition of either demyelinating agent induced a greater degree of myelin loss followed by incomplete remyelination in both cases. This failure to remyelinate was associated in both groups with a several-fold elevation in TNF-alpha and with modest increases in PDGF-AA and FGF-2 in the antibody-treated cultures. In contrast, macrophage supplementation to mature cultures in the absence of any demyelinating treatment resulted in enhanced accumulation of MBP associated with a promyelinative growth factor and TNF-alpha profile similar to that in aggregates enriched with macrophages at the outset of the culture period. Hence, effector elements of the adaptive immune response appear to override promyelinogenic in favor of proinflammatory macrophage factors in mature CNS aggregates, counteracting the potential for myelin repair. (C) 2003 Wiley-Liss, Inc.