| || |
|Title:||HARNESSING GLATIRAMER ACETATE-INDUCED BENEFICIAL INFLAMMATION FOR REPAIR|
| || |
|Authors/Affiliations:||1 Viktor Skihar*; 1 Claudia Silva; 1 Andrew Chojnacki; 1 Samuel Weiss; 1 V. Wee Yong; |
1 Hotchkiss Brain Institute and the Department of Clinical Neurosciences, University of Calgary, AB, Canada
| || |
|Content:||Objective: To develop means to enhance the generation of oligodendrocyte precursor cells (OPCs) and their maturation into oligodendrocytes with the capacity for remyelination. |
Background: Remyelination occurs in MS. While some MS subjects show extensive remyelination, many have limited repair capacity and therapeutic interventions are necessary. A prerequisite for remyelination is the formation of new OPCs, a process that is controlled by many growth factors. The delivery of single growth factors in experimental studies has largely failed to promote remyelination, and multiple growth factors may have to be delivered. Leukocytes are now recognized to be sources of several neurotrophic factors, so they could be used as potential delivery vehicles for trophic factors into the injured CNS. The challenge of harnessing beneficial inflammation is how to avoid its potential detrimental consequences. The MS medication, glatiramer acetate (GA), has been recognized to generate Type 2 monocytes and CD4+ T helper 2 (Th2) cells that are anti-inflammatory and non-toxic. Herein, we have addressed whether GA promotes repair in a mouse demyelinating model.
Design/Methods: Bone marrow-derived monocytes and lymph node-derived T cells were used in culture. Demyelination in mice in vivo was inflicted by the local injection of lysolecithin to the spinal cord.
Results: Monocytes treated with GA and GA-reactive Th2 cells produce the growth factors IGF-1 and BDNF. In culture, the conditioned medium from GA-reactive Th2 cells promotes the maturation of OPCs from neural stem cell progenies. Following lysolecithin demyelination, the daily treatment of mice with GA for 7 days elevates IGF-1 and BDNF levels around the injury site and increases the number of OPCs. The density of microglia/macrophages around the lesion site at day 7 is extensive and comparable in lysolecithin-demyelinated mice treated with GA or saline, but the cytokine milieu in GA-treated mice favored an anti-inflammatory one (high IL-5:IL-12 ratio). Preliminary data shows that boosting the immune responsiveness of mice with incomplete Freundís adjuvant led to increased remyelinating capacity in GA-treated mice when analysed at 28 days after the lysolecithin injury.
Conclusions/Relevance: These experiments highlight the feasibility of promoting neural repair through harnessing beneficial inflammation and suggest that the effectiveness of GA can be further promoted through optimized immune regulation.
| || |