Identification of new therapeutic targets for prevention of CNS inflammation

Abstract

Multiple sclerosis (MS) is a disease of complex pathologies, which involves infiltration by CD4⁺ and CD8⁺ T cells of and response within the central nervous system. Expression in the CNS of cytokines, reactive nitrogen species and costimulator molecules have all been described in MS. Notably, the cytokines IFN-γ and TNF are strongly expressed. Microglial cells in the CNS express costimulator molecules and it is assumed that they play a role in directing or inducing the T cell response. Transgenic experiments have tested the effects of overexpression of these molecules in mice and have shown that TNF has multiple effects in the CNS. These range from pro-inflammatory effects of soluble TNF signalling through one of its receptors TNF-RI, to protective/regenerative effects of membrane-associated TNF signalling through the other receptor, TNF-RII. Although IFN-γ induces nitric oxide production via the enzyme inducible nitric oxide synthase, which is immunosuppressive, IFN-γ is predominantly pro-inflammatory. In CNS disease in mice that involves CD8⁺ T cells, IFN-γ blockade is protective. Finally, microglial expression of the costimulator ligand B7.2 induces demyelinating pathology. Animal experiments therefore point to IFN-γ and costimulatory microglia as logical targets of therapy for MS. IFN-γ represents a more accessible target and should therefore be pursued at the earliest opportunity.

• altered peptide ligand
• astrocyte
• cytokine
• IFN-β
• IFN-γ
• microglia
• multiple sclerosis
• nitric oxide
• oligodendrocyte
• receptors
• T lymphocyte
• transgenic
• tumour necrosis factor