Local Immunomodulation with Anti-inﬂammatory Cytokine-Encoding Lentivirus Enhances Functional Recovery after Spinal Cord Injury

Molecular Therapy, 2018 · DOI: https://doi.org/10.1016/j.ymthe.2018.04.022 · Published: July 1, 2018

Spinal Cord Injury Regenerative Medicine Immunology

Simple Explanation

Trauma to the spinal cord can lead to permanent loss of sensory and motor function due to secondary inflammation that limits regeneration. This study explores using lentiviral transduction in multichannel bridges to express anti-inflammatory cytokines IL-10 and IL-4, aiming to modulate the neuroinflammatory microenvironment and enhance axonal regeneration. The multichannel bridges provide physical guidance for axonal outgrowth, while the cytokines are intended to reduce neuroinflammation, thus promoting nerve regeneration. The research examines gene expression, axon and myelin numbers, and locomotor function to evaluate the effectiveness of this approach. The combination of a multichannel bridge with IL-10 and IL-4 expression improved locomotor function after injury. These studies highlight the potential for localized immunomodulation to decrease secondary inflammation and enhance regeneration that may have numerous applications.

Study Duration

84 days

Participants

C57/BL6 female mice (6–8 weeks old)

Evidence Level

Not specified

Key Findings

1
Induced IL-10 and IL-4 expression decreased expression of pro-inflammatory genes and increased pro-regenerative genes relative to control. The anti-inflammatory factors led to increased numbers of axons and myelination.
2
The combination of a bridge with IL-10 and IL-4 expression improved locomotor function after injury, indicating the potential for localized immunomodulation to enhance regeneration.
3
Overexpression of anti-inﬂammatory factors inﬂuences macrophage polarization at the injury site. Localized expression of anti-inﬂammatory cytokines promotes axonal regeneration and axonal remyelination as a function of time.

Research Summary

The study investigates the effect of localized immunomodulation using lentiviral delivery of IL-10 and IL-4 from a multichannel PLG bridge on nerve regeneration after spinal cord injury. The hypothesis is that the bridge's architecture will synergize with the immunomodulation provided by the cytokines to attenuate inflammation and promote regeneration. The key findings include decreased expression of pro-inflammatory genes and increased pro-regenerative genes, increased numbers of axons and myelination, and improved locomotor function with the combined bridge and cytokine expression. The results suggest that providing a permissive environment for regeneration with a multichannel bridge, combined with localized anti-inflammatory cytokine gene delivery, may provide a novel therapeutic strategy to overcome a neuroinflammatory microenvironment for nerve regeneration after SCI.

Practical Implications

Therapeutic Strategy

Localized delivery of anti-inflammatory cytokines via lentiviral vectors within multichannel bridges represents a potential therapeutic strategy for spinal cord injury.

Immunomodulation

Targeting the neuroinflammatory microenvironment through immunomodulation can promote nerve regeneration and functional recovery.

Macrophage Polarization

Modulating macrophage polarization towards a pro-regenerative M2 phenotype is crucial for axonal regrowth and remyelination.

Study Limitations

1
Transgene expression requires a week to achieve significant levels, suggesting the need for earlier intervention to restrict acute immune response-mediated tissue damage.
2
The study is limited by the use of a mouse model, and results may not directly translate to human spinal cord injury.
3
Localized delivery of therapeutics to the injured spinal cord has been unable to achieve long-term expression of therapeutics without additional surgery procedures.

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