Modulating innate immune cells as a potential therapy for Multiple Sclerosis
There is an emerging consensus that the progression of disability in MS correlates with the accumulation of axonal degeneration, which in turn is influenced by the extent of demyelination and the loss of oligodendrocytes.
Current MS therapies, however, are anti-inflammatory, predominantly suppressing the adaptive immune response, and although they are efficient in limiting the relapses that characterise the early phase of MS, there is no clear evidence that they inhibit long-term progression.
There is, therefore, a clear need to develop new therapeutic methods that can improve repair and thus slow or prevent disability progression in Multiple Sclerosis. Therapies based around the transplantation of stem cells are a promising avenue for novel treatments to promote repair in MS, although evidence of the effectiveness of such strategies is limited and often contradictory. However, current approaches are principally aimed at cell replacement, usually of oligodendrocytes, the myelin producing cell of the central nervous system, to expedite myelin repair.
This project will test an alternative therapeutic strategy based upon the addition of reparative microglial cells in the context of established demyelination in a mouse model. Microglia, innate immune cells which are exclusively found within the central nervous system, are often activated during the clinical course of MS. Microglia can be either pathogenic (M1-like) or reparative (M2-like); the latter having a key role in phagocytosis of myelin debris and therefore providing an environment receptive to remyelination. Until recently there has been a lack of easy-to-use molecular signatures to unequivocally discriminate between M1-like and M2-like cells. However, is has recently been identified that Mertk, a cell surface receptor that mediates the phagocytosis of cellular debris, is exclusively expressed by reparative (M2-like) anti-inflammatory microglia. This discovery therefore provides a mechanism by which to purify and test the therapeutic efficacy of M2-like cells.
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