Tumour Necrosis Factor Neutralization in MS: a Cautionary Tale (Multiple Sclerosis) (Clinical Report)
The International MS Journal 2010, July, 17, 2
The International MS Journal
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Multiple sclerosis (MS) is thought to be an autoimmune process directed against one or more unidentified central nervous system (CNS) antigens. The inflammatory response that precedes MS relapses and continues across their course is characterized by increased expression of numerous cytokines. Tumour necrosis factor (TNF) is prominent among them. TNF protein and TNF mRNA are present within active MS demyelinating foci, even in those biopsied at disease onset and perhaps even those biopsied so early that demyelination has yet to begin. TNF presence correlates inversely with mature oligodendrocyte survival, (1,2) a finding consistent with a direct toxic effect of TNF for oligodendrocytes as has been shown in vitro (3) and in vivo. (4) TNF promotes astrocyte proliferation, (5) a finding germane to the reactive gliosis that becomes prominent as MS plaques evolve. TNF, released at low levels under normal circumstances by glia, positively regulates synaptic transmission in the brain and is required for normal cognitive function. Effects of TNF within the brain vary with cytokine concentration. Too little or too much can have negative consequences. Transgenic mice lacking TNF are cognitively impaired. (6) Mice can also be engineered to overexpress TNF in the brain. Mice of one overexpressing line develop spontaneous myelin pathology, mice of a second line develop experimental autoimmune encephalomyelitis (EAE) of exacerbated severity in response to immunization with myelin protein, while in mice of a third line, no pathology is evident. Mice of all three lines are cognitively impaired. (6,7) Excess TNF abruptly induces conduction block in axons. (8) Not surprisingly, TNF is widely held to contribute to CNS damage in MS. TNF synthesis by blood-derived mononuclear cells from MS patients increases prior to onset of exacerbations as compared with other times. (9-10) TNF mRNA is over-expressed by blood mononuclear cells from MS patients with active disease as opposed to stable patients or healthy controls. (11) These findings have been viewed as providing evidence in support of a disease-promoting role for TNF in MS. As we shall see, the situation is not so simple.
- 2,99 €
- Category: Health & Fitness
- Published: 01 July 2010
- Publisher: PAREXEL MMS Europe Ltd.
- Print Length: 17 Pages
- Language: English