- Paper Report
- Open Access
Suppression of autoimmunity by TNF
- Jose L Pablos1
© Biomed Central Ltd 2001
- Received: 26 July 2001
- Published: 26 July 2001
- Multiple sclerosis
- T cells
- TNF receptor p55
In rheumatoid arthritis (RA), tumor necrosis factor (TNF) is a major pathogenetic cytokine; consequently, TNF-blocking agents have been established as a successful therapy for RA. TNF induces a variety of cellular effects through specific receptors (p55 and p75) that are coupled to complex signal transduction pathways involving NF-?B, JNK and intracellular proapoptotic proteins. In addition to its strong proinflammatory effects, TNF may also exert potent immunosuppressive effects on T cells. Treatment with TNF inhibitors has been associated with autoimmune phenomena such as the development of antinuclear antibodies or lupus-like syndromes, and with the onset or flares of demyelinating syndromes, including multiple sclerosis (MS). MS is a disabling inflammatory disease of the central nervous system, considered to result from self-reactivity to myelin antigens. TNF has been implicated in the pathogenesis of MS but, paradoxically, its blockade may have both immune system and disease activating effects.
In TNF-deficient mice, myelin basic protein (MBP)-specific T-cell reactivity fails to regress. This leads to susceptibility to EAE in otherwise resistant H-2b mice. In contrast to wild-type C57BL/6 mice, which develop rapid onset disease, immunization of TNF-/- or p55p75-/- mice with myelin oligodendrocyte glycoprotein (MOG) led to delayed onset of EAE, but abnormally prolonged disease which failed to remit. This phenotype correlated with persistent T-cell responses and expansion of activated/memory T cells specific for myelin antigens. Interestingly, the beneficial long-term immunosuppressive effects of TNF that protect against chronic EAE do not require the p55 TNF receptor, as demonstrated in p55-/- mice, whereas the same receptor is necessary for the detrimental effects of TNF during the acute phase of the disease.
TNF-/-, p55p75-/-, p55-/- and control mice; immunization with MBP or MOG; histopathological analysis; flow cytometry; analysis of T cell proliferative responses
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