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Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Antigen-specific therapy promotes repair of myelin and axonal damage in established EAE
Chunhe Wang1, Bruce G Gold, Laurie J Kaler
1Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon, USA. wangch@ohsu.edu
Abstract:
Inflammation results in CNS damage in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. It is uncertain how much repair of injured myelin and axons can occur following highly selective anti-inflammatory therapy in EAE and MS. In this study, SJL/J mice with established EAE were treated successfully with an antigen-specific recombinant T cell receptor ligand (RTL), RTL401, a mouse I-A(s)/PLP-139-151 construct, after the peak of EAE. To define the mechanisms by which late application of RTL401 inhibits EAE, we evaluated mice at different time points to assess the levels of neuroinflammation and myelin and axon damage in their spinal cords. Our results showed that RTL401 administered after the peak of acute EAE induced a marked reduction in inflammation in the CNS, associated with a significant reduction of demyelination, axonal loss and ongoing damage. Electron microscopy showed that RTL-treated mice had reduced pathology compared with mice treated with vehicle and mice at the peak of disease, as demonstrated by a decrease in continued degeneration, increase in remyelinating axons and the presence of an increased number of small, presumably regenerative axonal sprouts. These findings indicate that RTL therapy targeting encephalitogenic T cells may promote CNS neuroregenerative processes.
Insights
Late treatment with a T cell receptor ligand (RTL) reduced central nervous system (CNS) damage in a multiple sclerosis model. This therapy promoted myelin repair and axonal regeneration, suggesting potential for neuroregeneration in MS.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Inflammation causes central nervous system (CNS) damage in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE).
- The extent of myelin and axonal repair after anti-inflammatory therapy in MS and EAE remains unclear.
Purpose of the Study:
- To investigate the mechanisms by which late-stage administration of a recombinant T cell receptor ligand (RTL401) inhibits EAE.
- To assess neuroinflammation, myelin damage, and axonal loss in the spinal cords of EAE mice treated with RTL401 after disease onset.
Main Methods:
- SJL/J mice with established EAE were treated with RTL401 (an I-A(s)/PLP-139-151 construct) after the peak of the disease.
- Spinal cords were analyzed at various time points to evaluate neuroinflammation, demyelination, and axonal damage using histology and electron microscopy.
Main Results:
- RTL401 treatment significantly reduced CNS inflammation, demyelination, and axonal loss in EAE mice.
- Electron microscopy revealed decreased degeneration, increased remyelination, and evidence of axonal regeneration (small sprouts) in RTL401-treated mice compared to controls.
Conclusions:
- Late-stage administration of RTL401 effectively inhibits EAE progression and reduces CNS pathology.
- Targeting encephalitogenic T cells with RTL therapy may promote neuroregenerative processes in the CNS, offering a potential therapeutic strategy for MS.
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