Targeted expression of IGF-1 in the central nervous system fails to protect mice from experimental autoimmune encephalomyelitis.
Insulin-like growth factor 1 (IGF-1) has been identified as a critical molecule in the induction of myelination in the central nervous system (CNS). Systemic injection of IGF-1 has been shown to have a varied and transiently protective effect on the clinical course of experimental autoimmune encephalomyelitis (EAE). Since systemic IGF-1 can also modulate peripheral immune lymphocytes, we examined whether a sustained and local delivery of IGF-1 into the spinal cord would have any influence on the chronic course of EAE in C57/BL6 mice. The capability of adeno-associated virus (AAV) to be retrogradely transported efficiently from muscle to motor neurons of the spinal cord was used to overcome the difficulty routinely encountered when attempting chronic delivery of molecules into the CNS. We demonstrate that AAV-mediated delivery of IGF-1 in CNS did not have any beneficial effect on the clinical course of EAE. Injection of AAV-IGF1 after induction of the disease worsened the clinical symptoms. Furthermore, CNS expression of IGF-1 did not affect the pathogenic anti-MOG T cell response, as examined by proliferation and cytokine secretion. Thus, enhanced expression of IGF-1 in the CNS during inflammation does not have a significant effect on myelination. These data have important implications for the potential use of IGF-1 in the treatment of multiple sclerosis.
Genoud
Stéphane
S
Laboratory of Genetics, The Salk Institute, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Maricic
Igor
I
Kumar
Vipin
V
Gage
Fred H
FH
D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006023:Glycoproteins; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D007334:Insulin-Like Growth Factor I