William Bailey, University if Kentucky, Lexington, USA

Promoting a Targeted Neuroprotective Immune Response

Funded in: 2013, 2014, 2015

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Problem: Spinal cord injury triggers a death wave that enlarges the injury.

Target: Specific immune cells, the M2 monocyte population, using newly designed viral constructs.

Goal: Increase the number of M2 cells to increase protection and save patient’s functions.

After spinal cord injuries (SCI) cell death triggers an inflammatory response followed by secondary damage which progressively enlarges the tissue damage and increases the extent of functional impairment. During this inflammatory reaction immune cells are activated and depending on the specific activation the cells result in divergent roles in the response to injury:

  • classically activation result in M1 cells
  • alternatively activation result in M2 cells.

The M1 phenotype is associated with greater cell loss and a greater progression in tissue damage, whereas an M2  phenotype may promote cell protection, regeneration, and plasticity. Unfortunately, after SCI the environment drives the immune response toward an M1 phenotype. One way to promote tissue protection could be to change the balance of these immune cells towards the M2 cells.
The switch to the different phenotypes is triggered by specific receptors of the cells, the “triggering receptor expressed on myeloid cells 2 (TREM2)” which plays an important role in regulating the M2 phenotype.

Preliminary data show that the characteristics of microglial cells can be changed by viral vector technology- viral vectors carrying specific characteristics infiltrate the cells and modulate their phenotype. Microglial cells transduced ex-vivo with a viral vector to over-express TREM2 were activated to M2 cells and retain the M2 phenotype after transplantation in the injured spinal cord.

The aim of this project is to develop viral vector constructs for a viable delivery system. The goal is to increase the portion of M2 cells in the lesion by overexpression of the TREM 2 receptor and to reduce the pathological progression of tissue damage.

The proposed project will take a first step to create an immune response that is neuroprotective and limits the death of neurons and glial cells to achieve regeneration of the injured nerve fibres. Further this could lead to a clinical therapy relevant to a broad spectrum of injuries in which microglia/macrophages are involved.