Possible therapeutic vaccines for canine myasthenia gravis: implications for the human disease and associated fatigue
F Shawn Galin, Cheryl L Chrisman, James R Cook Jr, Likang Xu, Patricia L Jackson, Brett D Noerager, Nathaniel M Weathington, J Edwin Blalock, F Shawn Galin, Cheryl L Chrisman, James R Cook Jr, Likang Xu, Patricia L Jackson, Brett D Noerager, Nathaniel M Weathington, J Edwin Blalock
Abstract
Myasthenia gravis (MG) is caused by T cell-dependent antibodies reactive with acetylcholine receptors. These autoreactive antibodies cause muscle weakness by interfering with neuromuscular transmission via removal of acetylcholine receptors from the neuromuscular junction as well as changing the architecture of the junction itself. Consequently, muscle fatigue is a debilitating aspect of MG often leading to more general feelings of tiredness not directly due to muscle weakness. We have previously described two peptides that are mimetics of antigen receptors on certain autoreactive T and B cells that are involved in MG. When used as vaccines in the rat model of MG, these peptides prevented and ameliorated disease and muscle fatigue by blunting acetylcholine receptor antibody responses. Such disease protection resulted from vaccine-induced anergizing antibodies against acetylcholine receptor-specific T and B cell antigen receptors. The present study prospectively evaluated the efficacy of these two vaccines in spontaneous acquired MG in pet dogs. When compared to historical controls that were prospectively studied, the vaccines increased the proportion of remitted dogs from 17 to 75%. In comparison to retrospectively studied historical controls that spontaneously remitted from MG, the vaccines accelerated the rate of decline in acetylcholine receptor antibody titers which resulted in a 3-fold decrease in the mean time to remission. These results are suggestive of a new type of targeted therapy that can drive autoimmune responses into long-term remission and possibly afford a means of determining whether correction of a physical cause of muscle weakness also corrects the perception of chronic, generalized fatigue.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1857319/bin/nihms-18629-0001.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1857319/bin/nihms-18629-0002.jpg)
Figure 3
Time course of AChR Ab…
Figure 3
Time course of AChR Ab levels in myasthenic nonvaccinated historical control dogs (A,…
Figure 4
A: Correlation between the time…
Figure 4
A: Correlation between the time relative to confirmed diagnosis (0 time) of the…
Figure 5
A: Comparison of the mean…
Figure 5
A: Comparison of the mean time (month ± SEM) to remission post confirmed…
- Adult onset acquired myasthenia gravis in three Great Dane littermates.Kent M, Glass EN, Acierno M, Shelton GD. Kent M, et al. J Small Anim Pract. 2008 Dec;49(12):647-50. doi: 10.1111/j.1748-5827.2008.00627.x. Epub 2008 Aug 5. J Small Anim Pract. 2008. PMID: 18684140
- Spontaneous remission in canine myasthenia gravis: implications for assessing human MG therapies.Shelton GD, Lindstrom JM. Shelton GD, et al. Neurology. 2001 Dec 11;57(11):2139-41. doi: 10.1212/wnl.57.11.2139. Neurology. 2001. PMID: 11739846
- Antibodies to the acetylcholine receptor in myasthenic dogs.Garlepp M, Farrow B, Kay P, Dawkins RL. Garlepp M, et al. Immunology. 1979 Aug;37(4):807-10. Immunology. 1979. PMID: 500127 Free PMC article.
- Myasthenia gravis and congenital myasthenic syndromes in dogs and cats: A history and mini-review.Shelton GD. Shelton GD. Neuromuscul Disord. 2016 Jun;26(6):331-4. doi: 10.1016/j.nmd.2016.03.002. Epub 2016 Mar 10. Neuromuscul Disord. 2016. PMID: 27080328 Review.
- Muscle autoantibodies in myasthenia gravis: beyond diagnosis?Meriggioli MN, Sanders DB. Meriggioli MN, et al. Expert Rev Clin Immunol. 2012 Jul;8(5):427-38. doi: 10.1586/eci.12.34. Expert Rev Clin Immunol. 2012. PMID: 22882218 Free PMC article. Review.
- Advances in autoimmune myasthenia gravis management.Wang S, Breskovska I, Gandhy S, Punga AR, Guptill JT, Kaminski HJ. Wang S, et al. Expert Rev Neurother. 2018 Jul;18(7):573-588. doi: 10.1080/14737175.2018.1491310. Epub 2018 Jul 4. Expert Rev Neurother. 2018. PMID: 29932785 Free PMC article. Review.
- Animal models for metabolic, neuromuscular and ophthalmological rare diseases.Vaquer G, Rivière F, Mavris M, Bignami F, Llinares-Garcia J, Westermark K, Sepodes B. Vaquer G, et al. Nat Rev Drug Discov. 2013 Apr;12(4):287-305. doi: 10.1038/nrd3831. Epub 2013 Mar 15. Nat Rev Drug Discov. 2013. PMID: 23493083 Review.
- Molecular recognition theory and sense-antisense interaction: therapeutic applications in autoimmunity.Hardison MT, Blalock JE. Hardison MT, et al. Front Biosci (Elite Ed). 2012 Jan 1;4(5):1864-70. doi: 10.2741/e508. Front Biosci (Elite Ed). 2012. PMID: 22202003 Free PMC article. Review.
- Comparative Study
- Evaluation Study
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Antibody Formation / immunology*
- Autoantibodies / immunology
- B-Lymphocytes / immunology
- Dog Diseases / drug therapy*
- Dog Diseases / immunology
- Dogs
- Fatigue / drug therapy
- Fatigue / etiology
- Fatigue / immunology
- Fatigue / veterinary*
- Female
- Male
- Myasthenia Gravis / complications
- Myasthenia Gravis / drug therapy
- Myasthenia Gravis / immunology
- Myasthenia Gravis / veterinary*
- Prospective Studies
- Receptors, Cholinergic / immunology*
- Remission Induction
- T-Lymphocytes / immunology
- Treatment Outcome
- Vaccines / immunology
- Vaccines / therapeutic use*
- Autoantibodies
- Receptors, Cholinergic
- Vaccines
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1857319/bin/nihms-18629-0003.jpg)
Figure 4
A: Correlation between the time…
Figure 4
A: Correlation between the time relative to confirmed diagnosis (0 time) of the…
Figure 5
A: Comparison of the mean…
Figure 5
A: Comparison of the mean time (month ± SEM) to remission post confirmed…
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1857319/bin/nihms-18629-0004.jpg)
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/1857319/bin/nihms-18629-0005.jpg)
Source: PubMed