The immune system is remarkably efficient in discriminating self from nonself and is equipped with an array of effector mechanisms designed to destroy foreign (nonself) entities. However, in autoimmune disease, the immune system mistakenly recognizes a self-tissue as foreign and initiates a destructive immune response against tissue-specific self "antigens". Autoimmunity accounts for a wide array of human diseases including arthritis, diabetes, systemic lupus erythematosus, myasthenia gravis, and multiple sclerosis among many others. Our research is focused upon the molecular and cellular basis of an autoimmune disease known as experimental autoimmune encephalitis (EAE). In this disease, experimental animals experience a paralytic autoimmune attack against the myelin sheath of central nervous system axons. Due to the clinical and histological features of this disease, EAE is widely regarded as a relevant animal model for human demyelinating diseases such as multiple sclerosis.
Our primary research interest is to advance a novel class of tolerogenic vaccines as a therapy for multiple sclerosis. These vaccines consist of cytokine-neuroantigen (NAg) fusion proteins that act to restore homeostatic self-tolerance in EAE. Antigen-specific regimens of tolerance induction promise to have improved efficacy compared to general immunosuppressive approaches because the anti-inflammatory activity of these tolerogenic vaccines is focused exclusively on the small percentage of T cells that cause disease. Thus, these vaccines obviate the need for global immune suppression. Furthermore, antigen-specific therapies are known to induce antigen-specific tolerance which is remembered by the immune system as a learned tolerance. Antigen-specific delivery regimens therefore will require temporary rather than chronic administration, will be effective at lower doses, and will exhibit superior efficacy and cost-effectiveness with fewer adverse side effects.
We have tested several of these vaccines in the EAE rodent model of multiple sclerosis. These vaccines were highly effective tolerogens and were able to inhibit a subsequent encephalitogenic challenge. These fusion proteins also were highly effective in stopping progression of disease when treatment was initiated during an ongoing attack. Our future research is dedicated to understanding the molecular and cellular mechanisms underlying the tolerogenic activity of these vaccines. We are also engaged in translational research to develop the clinical application of these vaccines for treatment of multiple sclerosis.
Wang, D., D. Ghosh, S. M. Islam, C. D. Moorman, A. E. Thomason, D. S. Wilkinson, and M. D. Mannie. 2016. IFN-beta Facilitates Neuroantigen-Dependent Induction of CD25+ FOXP3+ Regulatory T Cells That Suppress Experimental Autoimmune Encephalomyelitis. J. Immunol. PMID:27619998
Patial, S., A. D. Curtis, 2nd, W. S. Lai, D. J. Stumpo, G. D. Hill, G. P. Flake, M. D. Mannie, and P. J. Blackshear. 2016. Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies. Proc. Natl. Acad. Sci. U. S. A. 113: 1865-1870.PMID:26831084
Ghosh, D., A. D. Curtis, 2nd, D. S. Wilkinson, and M. D. Mannie. 2016. Depletion of CD4+ CD25+ regulatory T cells confers susceptibility to experimental autoimmune encephalomyelitis (EAE) in GM-CSF-deficient Csf2-/- mice. J. Leukoc. Biol.PMID:27256565
Islam, S. M., A. D. Curtis, 2nd, N. Taslim, D. S. Wilkinson, and M. D. Mannie. 2014. GM-CSF-neuroantigen fusion proteins reverse experimental autoimmune encephalomyelitis and mediate tolerogenic activity in adjuvant-primed environments: association with inflammation-dependent, inhibitory antigen presentation. J. Immunol. 193: 2317-2329. PMID:25049359Curtis, A. D., 2nd, N. Taslim, S. P. Reece, E. Grebenciucova, R. H. Ray, M. D. Rosenbaum, R. L. Wardle, M. R. Van Scott, and M. D. Mannie. 2014. The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species. PLoS One 9: e110048. PMID:25303101
Mannie Lab 2015