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Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro
1Department of Pathology (Neuropathology), Albert Einstein College of Medicine, New York, NY 10461.
Abstract:
Recombinant human tumor necrosis factor (rhTNF) has been tested for its effect on myelinated cultures of mouse spinal cord tissue. As controls, recombinant human interferon gamma (rhIFN) and interleukin-2 (rhIL-2) were tested, as well as T-cell supernatants, antigalactocerebroside serum, and normal culture medium. It was found that rhTNF induced delayed-onset (18-24 hr) oligodendrocyte necrosis and a type of myelin dilatation peculiar to this system. Some nerve fibers progressed to demyelination by 72 hours. The myelin dilatation was not reversible by return to normal feeding solution for 3 days. In contrast, rhIFN, rhIL-2, T-cell supernatants, and normal medium had little or no effect on cultures. This mechanism differs from other immune-mediated mechanisms in that it appears that a physiological (not structural) demyelination occurs initially without overt destruction of the myelin sheath. These observations are relevant to the evolution of the multiple sclerosis plaque: dysfunction of ionic channels might contribute to the eventual demise of oligodendrocytes and axons in the longstanding lesion.
Insights
Recombinant human tumor necrosis factor (rhTNF) causes delayed oligodendrocyte damage and myelin changes in mouse spinal cord cultures. This suggests a novel mechanism potentially relevant to multiple sclerosis pathology.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination.
- The precise mechanisms underlying MS plaque evolution, particularly early events, require further elucidation.
- Understanding the role of specific cytokines in demyelination is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of recombinant human tumor necrosis factor (rhTNF) on myelinated mouse spinal cord cultures.
- To compare the effects of rhTNF with other immune mediators like recombinant human interferon gamma (rhIFN), interleukin-2 (rhIL-2), and T-cell supernatants.
- To characterize the nature of myelin damage induced by rhTNF.
Main Methods:
- Myelinated mouse spinal cord tissue cultures were treated with rhTNF.
- Control treatments included rhIFN, rhIL-2, T-cell supernatants, antigalactocerebroside serum, and normal culture medium.
- Cultures were observed for oligodendrocyte necrosis, myelin dilatation, and demyelination over time.
Main Results:
- rhTNF induced delayed-onset oligodendrocyte necrosis (18-24 hours) and a unique myelin dilatation.
- Nerve fibers showed demyelination by 72 hours, which was irreversible.
- rhIFN, rhIL-2, T-cell supernatants, and normal medium had minimal effects on the cultures.
Conclusions:
- rhTNF triggers a distinct, physiological demyelination process without immediate structural destruction of the myelin sheath.
- This rhTNF-induced mechanism may offer insights into the early stages of multiple sclerosis plaque formation.
- Oligodendrocyte dysfunction and ionic channel disturbances could contribute to chronic demyelination and neurodegeneration in MS lesions.