B.S., University of Georgia
PhD Northwestern University
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.
Mannie MD, Curtis AD, 2nd. Tolerogenic vaccines for Multiple sclerosis. Hum Vaccin Immunother 2013, 9(5). PMID:23357858
Mannie MD, Blanchfield JL, Islam SM, Abbott DJ. Cytokine-neuroantigen fusion proteins as a new class of tolerogenic, therapeutic vaccines for treatment of inflammatory demyelinating disease in rodent models of multiple sclerosis. Front Immunol 2012, 3: 255. PMID:22934095
Abbott DJ, Blanchfield JL, Martinson DA, Russell SC, Taslim N, Curtis AD, et al. Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE). BMC Immunol 2011, 12: 72. PMID:22208499
Blanchfield JL, Mannie MD. A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC. J Leukoc Biol 2010, 87(3): 509-521. PMID:20007248
Mannie MD. Autoimmunity and asthma: The dirt on the hygiene hypothesis. Self Nonself 2010, 1(2): 123-128. PMID:21487514
Mannie MD, Abbott DJ, Blanchfield JL. Experimental autoimmune encephalomyelitis in Lewis rats: IFN-beta acts as a tolerogenic adjuvant for induction of neuroantigen-dependent tolerance. J Immunol 2009, 182(9): 5331-5341. PMID:19380780
Mannie M, Swanborg RH, Stepaniak JA. Experimental autoimmune encephalomyelitis in the rat. Curr Protoc Immunol 2009, Chapter 15: Unit 15 12. PMID:19347844
Mannie MD, Abbott DJ. A fusion protein consisting of IL-16 and the encephalitogenic peptide of myelin basic protein constitutes an antigen-specific tolerogenic vaccine that inhibits experimental autoimmune encephalomyelitis. J Immunol 2007, 179(3): 1458-1465. PMID:17641011
Mannie MD, Clayson BA, Buskirk EJ, DeVine JL, Hernandez JJ, Abbott DJ. IL-2/neuroantigen fusion proteins as antigen-specific tolerogens in experimental autoimmune encephalomyelitis (EAE): correlation of T cell-mediated antigen presentation and tolerance induction. J Immunol 2007, 178(5): 2835-2843. PMID:17312127
Mannie MD, Devine JL, Clayson BA, Lewis LT, Abbott DJ. Cytokine-neuroantigen fusion proteins: new tools for modulation of myelin basic protein (MBP)-specific T cell responses in experimental autoimmune encephalomyelitis. J Immunol Methods 2007, 319(1-2): 118-132. PMID:17188704