A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146
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 (EA...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01133/full |
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| author | Alessandra Consonni Sapna Sharma Karin Schön Cristina Lebrero-Fernández Elena Rinaldi Nils Yngve Lycke Fulvio Baggi |
| author_facet | Alessandra Consonni Sapna Sharma Karin Schön Cristina Lebrero-Fernández Elena Rinaldi Nils Yngve Lycke Fulvio Baggi |
| author_sort | Alessandra Consonni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T18:31:45Z |
| format | Article |
| id | doaj.art-c9df2d01fd6f40bb9ec10ad71108ae1b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T18:31:45Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c9df2d01fd6f40bb9ec10ad71108ae1b2022-12-21T19:30:02ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-09-01810.3389/fimmu.2017.01133287851A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146Alessandra Consonni0Sapna Sharma1Karin Schön2Cristina Lebrero-Fernández3Elena Rinaldi4Nils Yngve Lycke5Fulvio Baggi6Neurology IV, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, SwedenDepartment of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, SwedenDepartment of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, SwedenNeurology IV, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, SwedenNeurology IV, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, ItalyReinstating 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.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01133/fulltoleranceadjuvantvaccinationdendritic cellsmyasthenia gravisautoimmune disease |
| spellingShingle | Alessandra Consonni Sapna Sharma Karin Schön Cristina Lebrero-Fernández Elena Rinaldi Nils Yngve Lycke Fulvio Baggi A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146 Frontiers in Immunology tolerance adjuvant vaccination dendritic cells myasthenia gravis autoimmune disease |
| title | A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146 |
| title_full | A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146 |
| title_fullStr | A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146 |
| title_full_unstemmed | A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146 |
| title_short | A Novel Approach to Reinstating Tolerance in Experimental Autoimmune Myasthenia Gravis Using a Targeted Fusion Protein, mCTA1–T146 |
| title_sort | novel approach to reinstating tolerance in experimental autoimmune myasthenia gravis using a targeted fusion protein mcta1 t146 |
| topic | tolerance adjuvant vaccination dendritic cells myasthenia gravis autoimmune disease |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01133/full |
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