Identification of new therapeutic targets for prevention of CNS inflammation.
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-gamma 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-gamma induces nitric oxide production via the enzyme inducible nitric oxide synthase, which is immunosuppressive, IFN-gamma is predominantly pro-inflammatory. In CNS disease in mice that involves CD8(+) T cells, IFN-gamma blockade is protective. Finally, microglial expression of the costimulator ligand B7.2 induces demyelinating pathology. Animal experiments therefore point to IFN-gamma and costimulatory microglia as logical targets of therapy for MS. IFN-gamma represents a more accessible target and should therefore be pursued at the earliest opportunity.
Owens
Trevor
T
Neuroimmunology Unit, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4. trevor.owens@mcgill.ca
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D051940:B7-2 Antigen; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007167:Immunotherapy; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D016899:Interferon-beta / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D013792:Thalidomide / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D014611:Vaccination
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D016207:Cytokines; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013792:Thalidomide; D016899:Interferon-beta; D007371:Interferon-gamma