Treatment of experimental autoimmune encephalomyelitis with a neurotropic alphavirus vector expressing tissue inhibitor of metalloproteinase-2.
Prompted by our recent observations of increased MMP-8 and MMP-9 with simultaneous downregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-3 mRNA levels in the central nervous system (CNS) of mice with severe experimental autoimmune encephalomyelitis (EAE), we used Semliki Forest virus (SFV) to transfer and express recombinant murine TIMP-1-3 genes in the CNS. TIMP-1, TIMP-2 and TIMP-3 expression was confirmed in cultured cells and in the CNS of infected mice. Following intraperitoneal infection with 10(6) plaque-forming units (PFU) of SFV-TIMP, focal TIMP protein expression was achieved throughout the brain. Although already treatment with empty vector inhibited development of EAE to some extent, the expression of TIMP-2 by the virus significantly enhanced the inhibition. TIMP-3-administered mice also had lower disease grade, but the inhibition was not statistically significant. In contrast, SFV-TIMP-1 had no effect, similar to co-infection with TIMP-2 and TIMP-3. We found TIMP-2 expression also by non-infected CNS-resident cells surrounding the virus-positive areas, suggesting a bystander TIMP-2 induction. These data strengthen the view that matrix metalloproteinases are involved in the pathogenesis of EAE and provide clear evidence that virus-mediated delivery of their protein inhibitors can be effective in preventing the clinical disease. TIMPs might be candidates for novel treatment regimens in CNS autoimmune disorders, such as multiple sclerosis.
Nygårdas
P T
PT
Department of Biochemistry and Pharmacy, Abo Akademi University, Turku, Finland. pfuru@abo.fi
Grönberg
S A-M
SA
Heikkilä
J
J
Joronen
K
K
Sorsa
T
T
Hinkkanen
A E
AE
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D012672:Semliki forest virus / Q000235:genetics*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics
D012333:RNA, Messenger; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2