MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice

PNAS, 2015 · DOI: 10.1073/pnas.1521157112 · Published: December 29, 2015

Simple Explanation

Multiple sclerosis (MS) is an autoimmune disease where the body attacks the central nervous system. This study explores a treatment using MHC-mismatched mixed chimerism to eliminate clinical symptoms and prevent relapse of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of MS. The study found that using a specific conditioning regimen followed by transplantation of cells from MHC-mismatched donors eliminated clinical signs of EAE, reversed autoimmunity, and regenerated the myelin sheath. The cure was linked to the restoration of thymic function, specifically the deletion of autoreactive T cells and the increase in the production of regulatory T cells (Tregs), which are crucial for controlling autoimmune responses.

Study Duration

75 days

Participants

SJL/J and C57BL/6 mice

Evidence Level

Not specified

Key Findings

1
MHC-mismatched mixed chimerism eliminates clinical symptoms and prevents relapse of EAE in mice.
2
The treatment reverses autoimmunity, eliminates infiltrating immune cells in the spinal cord, and regenerates the myelin sheath.
3
The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4+ T cells and a significant increase in the percentage of Foxp3+ Treg cells.

Research Summary

This study investigates the use of MHC-mismatched mixed chimerism to treat experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for multiple sclerosis (MS). The findings demonstrate that this approach can eliminate clinical symptoms, prevent relapse, and reverse autoimmunity in EAE mice by restoring thymic function and promoting the production of regulatory T cells. The study suggests that MHC-mismatched mixed chimerism could be a curative therapy for progressive MS in humans, particularly for those who have not yet experienced significant axon damage.

Practical Implications

Potential Curative Therapy for MS

MHC-mismatched mixed chimerism could be developed into a curative therapy for highly active, progressing MS that is refractory to conventional treatments.

Targeted Immunomodulation

The study highlights the importance of thymic function and Treg cell production in controlling autoimmune diseases, suggesting potential targets for immunomodulatory therapies.

Clinical Translation

The use of clinically available reagents in the conditioning regimen makes this approach more readily translatable to human clinical trials.

Study Limitations

1
The study was conducted in mice and may not fully translate to human MS patients.
2
The treatment was most effective in early-stage EAE mice without significant axon damage, limiting its applicability to late-stage MS patients.
3
Further research is needed to fully understand the mechanisms behind the observed thymic changes and Treg cell expansion.

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