Journal Article

Targeting Insulin-Like Growth Factor 1 Leads to Amelioration of Inflammatory Demyelinating Disease

Libbey, Jane E., Trede, Nikolaus S., Cusick, Matthew F., Fujinami, Robert S.

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animals / Autoimmune diseases / Autoimmunity / Axon guidance / Axons - drug effects / Axons - pathology / Biology and Life Sciences / Care and treatment / Cell growth / Cell proliferation / Demyelinating diseases / Demyelination / Diagnosis / Encephalomyelitis, Autoimmune, Experimental - drug therapy / Encephalomyelitis, Autoimmune, Experimental - immunology / Experimental allergic encephalomyelitis / Female / Health aspects / Human behavior / Humans / Hydrazones - pharmacology / Hydrazones - therapeutic use / Inflammation - pathology / Insulin / Insulin-like growth factor I / Insulin-Like Growth Factor I - antagonists & inhibitors / Insulin-Like Growth Factor I - metabolism / Insulin-like growth factors / Interleukin-2 - metabolism / Kinases / Lymphocytes / Lymphocytes T / Medical treatment / Medicine and Health Sciences / Mice, Inbred C57BL / Molecular Targeted Therapy / Multiple sclerosis / Myelin / Myelin Proteolipid Protein - immunology / Pathogenesis / Peptide Fragments - immunology / Physiological aspects / Preservation / Quinolines - pharmacology / Quinolines - therapeutic use / Receptor, IGF Type 1 - metabolism / Recurrence / Research and Analysis Methods / Rodents / T cell receptors / T cells / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / Theilovirus - drug effects / Theilovirus - physiology