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A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using Targeted Fusion Protein, mCTA1-T146

Journal article
Authors A. Consonni
Sapna Sharma
Karin Schön
C. Lebrero-Fernandez
E. Rinaldi
Nils Y Lycke
F. Baggi
Published in Frontiers in Immunology
Volume 8
ISSN 1664-3224
Publication year 2017
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Language en
Links doi.org/10.3389/fimmu.2017.01133
Keywords tolerance, adjuvant, vaccination, dendritic cells, myasthenia gravis, autoimmune disease, cholera, regulatory t-cells, nicotinic acetylcholine-receptor, collagen-induced, arthritis, immature dendritic cells, nasal tolerance, alpha-subunit, treg cells, in-vitro, suppression, interleukin-27
Subject categories Immunology in the medical area

Abstract

Reinstating tissue-specific tolerance has attracted much attention as a means to treat autoimmune diseases. However, despite promising results in rodent models of autoimmune diseases, no established tolerogenic therapy is clinically available yet. In the experimental autoimmune myasthenia gravis (EAMG) model several protocols have been reported that induce tolerance against the prime disease-associated antigen, the acetylcholine receptor (AChR) at the neuromuscular junction. Using the whole AChR, the extracellular part or peptides derived from the receptor, investigators have reported variable success with their treatments, though, usually relatively large amounts of antigen has been required. Hence, there is a need for better formulations and strategies to improve on the efficacy of the tolerance-inducing therapies. Here, we report on a novel targeted fusion protein carrying the immunodominant peptide from AChR, mCTA1-T146, which given intranasally in repeated microgram doses strongly suppressed induction as well as ongoing EAMG disease in mice. The results corroborate our previous findings, using the same fusion protein approach, in the collagen-induced arthritis model showing dramatic suppressive effects on Th1 and Th17 autoaggressive CD4 T cells and upregulated regulatory T cell activities with enhanced IL10 production. A suppressive gene signature with upregulated expression of mRNA for TGF beta, IL10, IL27, and Foxp3 was clearly detectable in lymph node and spleen following intranasal treatment with mCTA1-T146. Amelioration of EAMG disease was accompanied by reduced loss of muscle AChR and lower levels of anti-AChR serum antibodies. We believe this targeted highly effective fusion protein mCTA1-T146 is a promising candidate for clinical evaluation in myasthenia gravis patients.

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Denna text är utskriven från följande webbsida:
http://www.gu.se/english/research/publication/?publicationId=257751
Utskriftsdatum: 2019-10-17