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 TGFβ, 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.
Highlights
Myasthenia Gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigability, which, in most cases, is the result of autoantibody production against the acetylcholine receptor (AChR) at the neuromuscular junction [1, 2]
Previous studies in the collagen-induced arthritis (CIA) model suggested that immune tolerance could be achieved in other models of autoimmune diseases, provided disease-relevant peptides were incorporated in the CTA1R9K-X-DD fusion protein [26]
We observed a striking suppression of the CD4+ T cell recall response to both TAChR and T146–162 peptide in the draining lymph nodes and spleen in mice treated with the mCTA1–T146 fusion protein, while PBS-treated mice showed robust responses (Figures 1B,C)
Summary
Myasthenia Gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigability, which, in most cases, is the result of autoantibody production against the acetylcholine receptor (AChR) at the neuromuscular junction [1, 2]. The disease is strongly associated with autoantibody production, the AChR-specific CD4+ T cells have a central regulatory role. MG patients have reduced levels of regulatory T cells (Tregs) [5,6,7,8] and restoring the levels of Tregs in the experimental autoimmune myasthenia gravis (EAMG) model suppressed disease [9]. Reinstating a functional Treg population could be a curative therapeutic intervention in MG [10]. Both Th1 and Th17 cells have been implicated in driving the autoimmune attack, but the precise contribution of the respective subset remains unclear [11,12,13]. Evidence in support of an involvement of Th17 cells in the EAMG model has been documented in several recent studies, while earlier studies, for example, in Tbet−/− mice demonstrated reduced susceptibility to EAMG as a consequence of fewer autoreactive Th1 cells [14]
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