Targeting insulin-like growth factor 1 leads to amelioration of inflammatory demyelinating disease.
In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
Matthew F
MF
Cusick
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
Jane E
JE
Libbey
Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America; Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
Nikolaus S
NS
Trede
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
Robert S
RS
Fujinami
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000473:pathology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D018991:Myelin Proteolipid Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012008:Recurrence; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D017945:Theilovirus / Q000187:drug effects / Q000502:physiology
C571887:1H-indole-3-carbaldehyde quinolin-8-yl-hydrazone; D006835:Hydrazones; D007376:Interleukin-2; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D011804:Quinolines; C435023:myelin proteolipid protein (139-151); D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1