Abstract
The role of the T helper (Th)17 pathway has been clearly demonstrated in the onset and progression of autoimmune diseases, where interleukin (IL)-23 is a key molecule in maintaining the response mediated by Th17 cells. As a consequence, recent strategies based on blocking the interaction between IL-23 and its receptor (IL-23R), for example the anti-p19 antibody tildrakizumab, have been developed to regulate the Th17 pathway from the initial stages of the disease. Here, a soluble (s)IL-23R cDNA was cloned in expression plasmids and viral vectors. The clinical efficacy of sIL-23R was evaluated in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis mice intravenously injected with a single dose of adeno-associated virus AAV8–sIL-23R vectors. Cytokine secretion was determined by multiplex assay, while histopathological analysis of the central nervous system was performed to study demyelination, inflammatory infiltration, and microglia and astroglia activation. We observed that administration of adeno-associated vector 8 encoding sIL-23R was associated with a significant disease improvement, including delay in the onset of the clinical signs; slower progress of the disease; interference with IL-23-mediated signal transducer and activator of transcription response by inhibiting of signal transducer and activator of transcription 3 phosphorylation; reduced demyelination and infiltration in the central nervous system; and lower astrocyte and microglia activation. Our results suggest that the use of vectors carrying sIL-23R to block the IL-23/IL-23R interaction may be a new therapeutic strategy for the treatment of multiple sclerosis.
Highlights
Multiple sclerosis (MS) is a chronic neurodegenerative and demyelinating autoimmune disease that affects an estimated 2.5 million people worldwide
For the purpose of finding new strategies in the fight against MS based on the control of the Th17 inflammatory axis, here we report that a single administration of adenoassociated virus (AAV) vectors carrying the coding sequence of soluble IL-23 receptor (IL-23R) delays the onset of the clinical signs, slows the progress of the disease, and reduces the inflammatory infiltration and demyelination in the central nervous system (CNS) in a myelin oligodendrocyte glycoprotein (MOG)-induced EAE mouse model
By analogy to human IL-23R4, we selected the sequence between the initiation ATG codon of exon 2 and the beginning of exon 10, just before the sequence corresponding to the transmembrane region (Fig. 1A)
Summary
Multiple sclerosis (MS) is a chronic neurodegenerative and demyelinating autoimmune disease that affects an estimated 2.5 million people worldwide. The role of the T helper (Th) pathway has been demonstrated in the development of MS, where interleukin (IL) is a key molecule in maintaining the response mediated by Th17 cells [1,2,3]. Patients with MS had more Th17 cells in the cerebrospinal fluid than patients with noninflammatory neurological diseases, suggesting their recruitment or enrichment to sites of inflammation in MS [5]. It is noteworthy that adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-specific Th17 cells reproduces experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inhibition of IL-23 may be a strategy to control the deregulation of the Th17 pathway during the initial stages of the disease and the evolution of the inflammatory autoimmune response
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
