Abstract
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.
Highlights
Multiple sclerosis (MS) is the most prevalent autoimmune disease of the central nervous system (CNS) in young adults
We found that LDK reduced insulin-like growth factor-1 receptor (IGF-1R) signaling, which is upstream of phosphatidylinositol 3 kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR), and arrested myelin-specific T cell proliferation
Incubation of cultures with both LDK and aIR3 led to inhibition of the suppressive effect of LDK, resulting in the restoration of T cell proliferation in response to PLP139–151 peptide, suggesting that LDK binds to IGF-1R (Figure 2). These results demonstrate that aIR3 and LDK neutralize or compete with each other suggesting that both LDK and aIR3 bind to the same or overlapping regions on IGF-1R
Summary
Multiple sclerosis (MS) is the most prevalent autoimmune disease of the central nervous system (CNS) in young adults. This inflammatory demyelinating disease is characterized by a proinflammatory response directed against ‘‘self’’ CNS antigens. A variety of immune cells have been implicated in MS pathogenesis including monocytes/macrophages, activated glial cells and autoreactive T cells [1,2,3]. EAE can be initiated through the adoptive transfer of myelin-specific T cells or by injection of a variety of CNS proteins or peptides with adjuvants [5]. In EAE, the sex, age and strain of the animal, as well as the protein/peptide used for inoculation, can determine the clinical course and pathologic features of disease [5]
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