Mark D. Mannie
Professor
BS, University of Georgia
PhD Northwestern University
Phone: 252-744-2701
Fax: 252-744-3104
Email: manniem@ecu.edu
ORCID Profile
Research
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 self-tissues as foreign antigens and initiates a destructive immune response against tissue-specific self “antigens”. Autoimmunity accounts for a wide array of human diseases including Rheumatoid Arthritis, Type I Diabetes, Systemic Lupus Erythematosus, Myasthenia Gravis, Crohn’s Disease, and Multiple Sclerosis among many others. As a disease class, autoimmune diseases include well over 150 distinct diseases that collectively afflict 10’s of millions of Americans. Our research is focused upon the molecular and cellular basis of an autoimmune disease known as Experimental Autoimmune Encephalomyelitis (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 is designed to advance a novel class of tolerogenic vaccines as a therapy for Multiple Sclerosis and other autoimmune diseases. Tolerogenic vaccines will be superior to broad-acting immunosuppressive drugs because tolerogenic vaccines exclusively inhibit the small percentage of autoreactive T cells that cause autoimmune disease without affecting the vast majority of other T cells that mediate host defense against infectious disease pathogens. Thus, tolerogenic vaccines offer a path to achieve qualitative advancements in therapeutic specificity for autoimmune disease. Because tolerogenic vaccines work by restoring immune tolerance to tissue-specific self-antigens, tolerogenic vaccines will require temporary rather than chronic administration, will be effective at lower doses, will exhibit superior efficacy and cost-effectiveness with fewer adverse side effects, and will obviate the need for chronic, global immune suppression. Because tolerogenic vaccines are vaccines and not drugs, the prediction is that a single vaccine series will elicit immune ‘memory’ that will be maintained by the immune system as a learned tolerance over the course of decades. We have tested two tolerogenic vaccine platforms in the EAE rodent model of Multiple Sclerosis. These vaccines were highly effective tolerogens that inhibited a subsequent encephalitogenic challenge and thereby prevented a future autoimmune attack. These tolerogenic vaccines also stopped progression of disease when treatment was first initiated during an ongoing paralytic autoimmune 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 advance clinical application of these vaccines for treatment of Multiple Sclerosis and other autoimmune diseases.
Tolerogenic vaccines restore self-tolerance by eliciting expansion and differentiation of a specialized FOXP3+ subset of regulatory T lymphocyte (Tregs), which express FOXP3 as the master transcription factor. This FOXP3+ Treg subset is essential for homeostatic self-tolerance because genetically-engineered mice that lack FOXP3+ Tregs succumb to systemic fatal autoimmune disease. FOXP3+ Tregs are deficient in many autoimmune diseases including Multiple Sclerosis, and we are testing the hypothesis that Tregs can be directly used to treat autoimmune disease. We have shown that via autologous adoptive immunotherapy protocols, Tregs obtained from donor mice and expanded ex vivo reverse autoimmune disease when infused back into syngeneic recipients. We are the first laboratory to successfully cultivate long-term continuous lines of FOXP3+ Tregs that mediate adoptive transfer of tolerance capable of reversing ongoing severe autoimmune disease. Ongoing research programs are focused on understanding optimal strategies for longterm propagation of antigen-specific Tregs in human and rodent systems.
Overall, our research focuses on two tolerogenic vaccine platforms coupled with a strong focus on the phenotype and function of continuous human and rodent FOXP3+ Treg lines. We are also developing a novel therapeutic platform to treat COVID-19 that will provide SARS CoV-2-specific, variant-independent therapy to stop viral infection while reversing pathogenic inflammation.
Selected Publications
Moorman CD, Bastian AG, DeOca KB, Mannie MD. A GM-CSF-neuroantigen tolerogenic vaccine elicits inefficient antigen recognition events below the CD40L triggering threshold to expand CD4+ CD25+ FOXP3+ Tregs that inhibit experimental autoimmune encephalomyelitis (EAE). J Neuroinflammation. 2020;17(1):180. Epub 2020/06/12. doi: 10.1186/s12974-020-01856-8. PubMed PMID: 32522287; PMCID: PMC7285464
Mannie MD, DeOca KB, Bastian AG, Moorman CD. Tolerogenic vaccines: Targeting the antigenic and cytokine niches of FOXP3+ regulatory T cells. Cell Immunol. 2020;355:104173. Epub 2020/07/28. doi: 10.1016/j.cellimm.2020.104173. PubMed PMID: 32712270.
DeOca KB, Moorman CD, Garcia BL, Mannie MD. Low-zone IL-2 signaling: Fusion proteins containing linked CD25 and IL-2 domains sustain tolerogenic vaccination in vivo and promote dominance of FOXP3+ Tregs in vitro. Front Immunol. 2020;11:541619. Epub 2020/10/20. doi: 10.3389/fimmu.2020.541619. PubMed PMID: 33072087; PMCID: PMC7538601.
Moorman CD, Curtis AD, 2nd, Bastian AG, Elliott SE, Mannie MD. A GMCSF-Neuroantigen tolerogenic vaccine elicits systemic lymphocytosis of CD4+ CD25high FOXP3+ regulatory T cells in myelin-specific TCR transgenic mice contingent upon low-efficiency T cell antigen receptor recognition. Front Immunol. 2018;9:3119. Epub 2019/01/29. doi: 10.3389/fimmu.2018.03119. PubMed PMID: 30687323; PMCID: PMC6335336.
Wilkinson DS, Ghosh D, Nickle RA, Moorman CD, Mannie MD. Partial CD25 antagonism enables dominance of antigen-inducible CD25high FOXP3+ regulatory T cells as a basis for a Treg-based adoptive immunotherapy. Front Immunol. 2017; https://doi.org/10.3389/fimmu.2017.01782. PubMed PMID: 29312311; PMCID: 5735073.
Wang D, Ghosh D, Islam SM, Moorman CD, Thomason AE, Wilkinson DS, Mannie MD. IFN-beta facilitates neuroantigen-dependent induction of CD25+ FOXP3+ regulatory T cells that suppress Experimental Autoimmune Encephalomyelitis. J Immunol. 2016; 197:2992-3007. Epub 2016/09/14. doi: 10.4049/jimmunol.1500411. PubMed PMID: 27619998; PMCID: 5101178
Ghosh D, Curtis AD, 2nd, Wilkinson DS, Mannie MD. Depletion of CD4+ CD25+ regulatory T cells confers susceptibility to experimental autoimmune encephalomyelitis (EAE) in GM-CSF-deficient Csf2-/- mice. J Leukoc Biol. 2016;100:747-60. Epub 2016/06/04. doi: 10.1189/jlb.3A0815-359R. PubMed PMID: 27256565.
Islam SM, Curtis AD, 2nd, Taslim N, Wilkinson DS, Mannie MD. 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. 2014;193(5):2317-29. Epub 2014/07/23. doi: 10.4049/jimmunol.1303223. PubMed PMID: 25049359; PMCID: PMC4137761.
Curtis AD, 2nd, Taslim N, Reece SP, Grebenciucova E, Ray RH, Rosenbaum MD, Wardle RL, Van Scott MR, Mannie MD. The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species. PLoS One. 2014;9(10):e110048. Epub 2014/10/11. doi: 10.1371/journal.pone.0110048. PubMed PMID: 25303101; PMCID: PMC4193844.
Mannie MD, Curtis AD, 2nd. Tolerogenic vaccines for Multiple sclerosis. Hum Vaccin Immunother. 2013;9(5):1032-8. Epub 2013/01/30.
PubMed 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. Epub 2012/08/31. doi: 10.3389/fimmu.2012.00255. PubMed PMID: 22934095; PMCID: PMC3422719.
Abbott DJ, Blanchfield JL, Martinson DA, Russell SC, Taslim N, Curtis AD, Mannie MD. 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. Epub 2012/01/03. doi: 10.1186/1471-2172-12-72. PubMed PMID: 22208499; PMCID: PMC3261124.
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):509-21. Epub 2009/12/17. doi: 10.1189/jlb.0709520. PubMed PMID: 20007248; PMCID: PMC2830126.
Staff
| Name | Title | Location | Phone | |
|---|---|---|---|---|
| Williford, Chandler | Research Specialist | Brody 5W-41 | 252-744-2713 | |
 | Jabbour, Hoda | Doctoral Candidate | Brody 5W-41 | 252-744-2713 |
 | Sneed, Sunny | Doctoral Student | Brody 5W-41 | 252-744-2713 |
| Gold, Mason | Volunteer | Brody 5W-41 | 252-744-2713 | |
| Johnson, Benjamin | Volunteer | Brody 5W-41 | 252-744-2713 | |
| Sampson, Noah | Volunteer | Brody 5W-41 | 252-744-2713 | |
| Smallwood, Christian | Volunteer | Brody 5W-41 | 252-744-2713 |