De rol van groeifactoren en ontregelende cytokinen bij multiple sclerose
06 / 1999 - 10 / 2004
Multiple sclerosis (MS) is the most common human demyelinating disease. Its pathology is characterized by multifocal areas of demyelination (lesions) in the central nervous system (CNS). Until now the cause of MS is still unknown, although several lines of evidence suggest that immunological phenomena play a role in the course. Recent evidence shows that cytokines are synthesized in the CNS. It is widely accepted that there is an integrated communication between the resident immune cells of the CNS and the periphery. Microglia and astrocytes are the two major cell types that produce cytokines in te CNS. Together they can govern a resident innate immune system by direct glial-immune cell interactions and by a CNS specific profile of cytokine production. In a recently published paper we have shown that the anti-inflammatory cytokines IL-10 and IL-4 have specific patterns of protein localization and protein expression in MS lesions at different stages of development. Moreover, prominent IL-10R and IL-4R expression was observed in (chronic) active MS lesions. These results indicate that IL-10 and IL-4 have an active role in CNS immune responses and that both IL-10 and IL-4 and their receptors participate in processes that eventually lead to the formation of chronic MS lesions. These results further suggest that as a consequence of the specific cytokine profile in the different MS lesion stages, more research on the specific functions of IL-10 and IL-4 is crucial before therapeutic strategies involving the use of anti-inflammatory cytokines in MS can be developed. Demyelinating diseases such as MS lead to prolonged neurological impairment. These symptoms are caused by focal destruction of myelin sheaths surrounding axons and/or oligodendrocytes in the CNS. The frequency of this disease and the relative paucity of spontaneous myelin repair account for considerable interest in mechanisms of CNS remyelination and in discovering therapeutic measures to enhance this process. Oligodendrocyte lineage cell proliferation and/or migration to repopulate demyelinated lesions may be regulated by growth factors. Several in vitro studies have indicated the involvement of the platelet-derived growth factor (PDGF) in inducing increased proliferation and migration of oligodendrocyte progenitors. In order to get more insight into the potential for PDGF A/B in repopulating demyelinated MS lesions, immunocytochemistry is performed on MS lesions at different stages of development. PDGFalphaR is used as a marker for oligodendrocyte progenitors. In addition, in situ hybridisation for proteolipid protein (PLP) mRNA in combination with an immunohistochemical staining for PLP was performed to identify (remyelinating) mature oligodendrocytes. Moreover, we are currently investigating the regulation of CC, CXC and CX3C chemokine expression by proinflammatory and anti-inflammatory cytokines in human adult astrocytes and microglial cells.