One of the main aims of this project is to generate an advanced humanized mouse model for multiple sclerosis (MS). MS is an autoimmune disease that specifically attacks the brain and spinal cord of the central nervous system (CNS) in humans, causing inflammation and loss of myelin. Myelin is the protective sheath that wraps neuronal axons and its loss in MS exposes neuronal cells to toxic the products of inflammation leading to neuronal damage.

 

In MS, immune cells in the blood are believed to be triggered by an unknown event to see CNS as a foreign tissue (non-self) and to mediate an autoimmune attack starting from very early in disease, even before the patient notices any neurological symptoms. Nevertheless, the importance of blood immune cells in disease initiation has not yet been scientifically proven.

 

In this project we wanted to test whether the transplantation of immune cells from blood samples of MS patients could induce disease with characteristics of MS in mice, for two main reasons: a) to prove that MS is indeed an autoimmune disease, b) to generate an advanced “humanized” mouse model for MS which would have several important advantages over other models including the ability to experimentally test human-specific drugs before their use in humans.

 

In collaboration with neurologists in a local MS clinic, we chose several MS patients as potential candidates for donors of blood samples. Typically, these patients were of the DRB1*1501 genotype, which is a gene associated with susceptibility to MS, and blood samples were taken when the patients were in an active phase of disease. Patients were fully informed of the procedures and scientific aims of the project and gave their written consent before enrolment. Subsequently, a small blood sample was taken and immune cells (peripheral blood monocytes, PBMC) were isolated in the laboratory and characterized for cellular composition by flow cytometry. These cells were then transplanted into groups of B2m-NOG immunodeficient mice. All mice were successfully transplanted with human immune cells and then monitored over time for the development of spontaneous disease, or increased susceptibility to experimental models of MS. The results of this experiment are currently being analysed for immune system function, histopathological and behavioural changes.

 

PUBLICATIONS RELATED TO THE PROJECT

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1. A. Dagkonaki, M. Avloniti, M. Evangelidou, I. Papazian, I. Kanistras, V. Tseveleki, F. Lampros, T. Tselios, L.T. Jensen, W. Möbius, T. Ruhwedel, M.E. Androutsou, J. Matsoukas, M. Anagnostouli, H. Lassmann., L. Probert*. Mannan-MOG35-55 Reverses Experimental Autoimmune Encephalomyelitis, Inducing a Peripheral Type 2 Myeloid Response, Reducing CNS Inflammation, and Preserving Axons in Spinal Cord Lesions. Front. Immunol., 2020, 11: 575451. https://doi.org/10.3389/fimmu.2020.575451 (open access)

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2. M.E. Androutsou, A. Nteli, A. Gkika, M. Avloniti, A. Dagkonaki, L. Probert, T. Tselios*, S.G. Grdadolnik*. Characterization of Asparagine Deamidation in Immunodominant Myelin Oligodendrocyte Glycoprotein Peptide Potential Immunotherapy for the Treatment of Multiple Sclerosis. Int. J. Mol. Sci., 2020, 21(20): 7566. https://doi.org/10.3390/ijms21207566. (open access)

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3. A. Dagkonaki, A. Papalambrou, M. Avloniti, A. Gkika, M. Evangelidou, M.E. Androutsou, T. Tselios, L. Probert. Maturation of circulating Ly6ChiCCR2+ monocytes by mannan-MOG induces antigen-specific tolerance and reverses autoimmune encephalomyelitis. Front. Immunol., 2022, 13: 972003 (open access)  https://doi.org/10.3389/fimmu.2022.972003.

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CONFERENCES PARTICIPATION

 

1. Dagkonaki A, Avloniti M, Androutsou M, Tselios T, Probert L. (2019). Peripheral T cell tolerance and protection against EAE by mannan-conjugated myelin autoantigens are not mediated by expansion of myeloid-derived suppressor cells. Presented at the 17th European School of Neuroimmunology (ESNI), Amsterdam, The Netherlands, July 16-19, 2019.

 

2. Δαγκωνάκη Α, Αυλωνίτη Μ, Ανδρούτσου Μ, Τσέλιος Θ, Probert L. (2019). Η περιφερική ανοχή των Τ κυττάρων και η προστασία από ΠΑΕ από τα συζευγμένα με μαννάνη πεπτίδια μυελίνης δεν μεσολαβείται από την επαγωγή των μυελοειδών κατασταλτικών κυττάρων. Παρουσιάστηκε στο 6ο Πανελλήνιο Συνέδριο της Ελληνικής Ακαδημίας Νευροανοσολογίας (ΕΛΛ.Α.ΝΑ), Θεσσαλονίκη, 12-15 Δεκεμβρίου, 2019.

 

3. Dagkonaki A, Avloniti M, Tselios T, Androutsou M, Probert L. (2021). A mannan-conjugated myelin antigen inhibits the induction of CNS autoimmunity by CD11b+Ly6Chi monocytes. Presented at the 15th International Congress of Neuroimmunology, France (virtual), November 8-12, 2021.

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4. A. Gkika, M.E. Androutsou, P. Katsougkraki, A. Aletras, T. Tselios. Analysis of mannan (polymannose)-peptide conjugate by competitive ELISA. Presented at the 36th European Peptide Symposium (EPS) & 12th International Peptide Symposium (IPS), Sitges, Barcelona, August 28- September 02, 2022.

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5. M.Ε. Androutsou, A. Nteli, A. Gkika, M. Avloniti, A. Dagkonaki, D. Zisimopoulos, L. Probert, S. Grdadolnik4, T. Tselios. Stability profile of Myelin Oligodendrocyte Glycoprotein Peptide in solid and liquid state. Presented at the 36th European Peptide Symposium (EPS) & 12th International Peptide Symposium (IPS), Sitges, Barcelona, August 28- September 02, 2022.

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6. A. Gkika, N. Zoupanou, M.E. Androutsou, T. Mavromoustakos, T. Tselios. NMR structural elucidation of mannan (polymannose) conjugate with the myelin oligodendrocyte glycoprotein 35-55 epitope (MOG35-55). Presented at the 36th European Peptide Symposium (EPS) & 12th International Peptide Symposium (IPS), Sitges, Barcelona, August 28- September 02, 2022.