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Prog Neurobiol. 2009 Dec;89(4):359-68. doi: 10.1016/j.pneurobio.2009.09.005. Epub 2009 Oct 1.

Restoring immune suppression in the multiple sclerosis brain.

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  • 1Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.


Multiple sclerosis is a very disabling inflammatory demyelinating disease of the brain of unknown etiology. Current therapies can reduce new lesion development and partially prevent clinical disease activity, but none can halt the progression, or cure the disease. We will review current therapeutic strategies, which are mostly discussed in literature in terms of their effective inhibition of T cells. However, we argue that many of these treatments also influence the myeloid compartment. Interestingly, recent evidence indicates that myelin phagocytosis by infiltrated macrophages and activated microglia is not just a hallmark of multiple sclerosis, but also a key determinant of lesion development and disease progression. We reason that severe side effects and/or insufficient effectiveness of current treatments necessitates the search for novel therapeutic targets, and postulate that these should aim at manipulation of the activation and phagocytic capacity of macrophages and microglia. We will discuss three candidate targets with high potential, namely the complement receptor 3, CD47-SIRPalpha interaction as well as CD200-CD200R interaction. Blocking the actions of complement receptor 3 could inhibit myelin phagocytosis, as well as migration of myeloid cells into the brain. CD47 and CD200 are known to inhibit macrophage/microglia activation through binding to their receptors SIRPalpha and CD200R, expressed on phagocytes. Triggering these receptors may thus dampen the inflammatory response. Our recent findings indicate that the CD200-CD200R interaction is the most specific and hence probably best-suited target to suppress excessive macrophage and microglia activation, and restore immune suppression in the brain of patients with multiple sclerosis.

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