Tumour necrosis factor and anti-tumour necrosis factor approach to inflammatory demyelinating diseases of the central nervous system

Open Access
Publisher Website
Google Scholar
Abstract
An initial interest of TNFα involvement in the pathomechanisms of multiple sclerosis was generated after demonstration that TNFα was capable of inducing delayed onset myelin dilatation and subsequent gradual myelin degradation in organotypic nerve tissue cultures.5 The organotypic nerve tissue cultures have been established from spinal cord tissue explanted from mice embryos. Several cytokines, TNFα, interferon γ, interleukin 1, interleukin 2, interleukin 6 were added to spinal cord cultures at a time when myelination was well advanced. The cultures were examined in living state and after fixation by light and electron microscopy. In the living state, cultures exposed to TNFα showed selective damage to myelin. By light microscopy, myelinated fibres exhibited dilatations of myelin sheath. These swellings were regularly spaced along affected fibres and appeared after 18 hours of exposure. Withdrawal of TNFα did not reverse the effect. Instead, more advanced myelin degradation was observed. Light microscopy of epoxy sections revealed that the myelin swelling involved an increase in the periaxonal space in such a way as to leave the axon intact but in large part separating it from its myelin sheaths. Oligodendroglia displayed less cytoplasm than usual and had fewer processes, in comparison with control cultures. By electron microscopy, it could be seen that within the dilated myelin sheaths, the axon was closely applied unilaterally, resting in a furrow of oligodendroglial cytoplasm. At the early stage of TNF induced changes, the myelin sheath was affected to a lesser degree, a normal periodicity was usually retained, presumably attributable to myelin slippage, and circumferential contact with the axon was lost, leaving a wide periaxinal space. At later time points, the majority of myelin sheaths progressed to degeneration, whereupon the debris was phagocytosed by surrounding reactive astrocytes. Astrocytes displayed considerable hypertrophy. Spinal cord explants treated with other cytokines showed few pathological alternations and were indistinguishable from control cultures.