key: cord-1027344-3ntuoyvc authors: Apostolopoulos, Vasso; Rostami, Abdolmohamad; Matsoukas, John title: The Long Road of Immunotherapeutics against Multiple Sclerosis † date: 2020-05-11 journal: Brain Sci DOI: 10.3390/brainsci10050288 sha: 79307a8fe925379fd6eb2d1197d3b36cf21d851c doc_id: 1027344 cord_uid: 3ntuoyvc This commentary highlights novel immunomodulation and vaccine-based research against multiple sclerosis (MS) and reveals the amazing story that triggered this cutting-edge MS research in Greece and worldwide. It further reveals the interest and solid support of some of the world’s leading scientists, including sixteen Nobel Laureates who requested from European leadership to take action in supporting Greece and its universities in the biggest ever financial crisis the country has encountered in the last decades. This support endorsed vaccine-based research on MS, initiated in Greece and Australia, leading to a worldwide network aiming to treat or manage disease outcomes. Initiatives by bright and determined researchers can result in frontiers science. We shed light on a unique story behind great research on MS which is a step forward in our efforts to develop effective treatments for MS. It was realized and clearly understood by the governments in Greece five years ago, and especially now, during this period of COVID-19 pandemic, the necessity for research, as first priority in their policies, for innovation, development and growth. Greece has suffered a lot the last decade from recession. Initiatives by eminent scientists were taken to support research in Greece, with remarkable positive outcomes. Fifteen Nobel Laureates cosigned the "Support for Greece" petition that was addressed by Nobel Laureate Professor Harald zur Hausen, on 14 December 2015, to the European leadership (Jean-Claude Juncker, Martin Schulz and Donald Tusk), pleading for the support for research in universities and to the country. The first to sign was the DNA discoverer Nobel Laureate Professor James Watson, who also sent a letter to the then President of the USA, Mr. Barack Obama, urging him to support Greece [1] . This petition to support research and universities in Greece led to the Hellenic Foundation for Research and Innovation (HFRI) to spur economic development. The European Investment Bank co-financed the creation of the HFRI fund with the Ministry of Finance. Professor Costas Fotakis, Alternate Minister of Research and Technology then, has greatly contributed to the establishment of HFRI. The HFRI fund launches regular calls for all scientists at all stages in support of their research. The "Support for Greece" petition, which was co-signed by the Nobel Laureates and led to the HFRI fund, was a joint initiative between Professor John Matsoukas from the of the consortium. In addition, his team developed novel altered peptide ligands of myelin peptides. The linear and cyclic peptides, native or as altered peptide ligands, were evaluated for stability in vitro, binding affinities to major histocompatibility complex class II, efficacy in mice and rats and to human peripheral blood mononuclear cells from patients with MS by various consortium groups [6, [12] [13] [14] [22] [23] [24] [25] [26] [27] [28] . Professor Vasso Apostolopoulos (immunologist and crystallographer), who had developed a novel antigen delivery system against breast and ovarian cancer [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] , which were translated into human clinical trials [44] [45] [46] [47] [48] , applied her insights into MS research [26, [49] [50] [51] [52] [53] [54] . The delivery system specifically targets dendritic cells and, when applied to myelin peptides (cyclic, linear and altered peptide ligands), was able to modulate immune responses from pro-inflammatory to anti-inflammatory, with protection and reversal of EAE in animal models and altered cytokine profile in peripheral blood mononuclear cells isolated from patients with MS [26, [49] [50] [51] [52] [53] [54] . Over 10 candidate immunotherapeutics have been developed and are justified for their use in phase I human clinical trials. Dr. Elizabeth Matsoukas can justifiably be proud of what she has achieved. Her pain was translated into promising global research to fight the disease. Her dream to see novel immunotherapeutics development against the disease is very close to being materialized. At last, she has seen research due to her case flourish globally. Elizabeth was honored by the Greek Academy of Athens for her dissertation and in 2018, by His Excellency, the President of the Hellenic Democracy, Mr. Prokopis Pavlopoulos, for her initial research and for being the inspiration, the spur and the motivating power of this research. In a special ceremony on 22 September 2018, in Amaliada (province of Ilida), celebrating 20 years of Medicinal Chemistry excellence in Greece, she was awarded by the president with a DNA-inspired plague made by famous sculptor Eustathios Leontis. Standing-ovation applause for her contribution was an emotional moment. In this special ceremony, the protagonists of this MS research, Professors Apostolopoulos, Rostami and Matsoukas, were also awarded, as well Professor Harald zur Hausen, for his contribution to science and society. In addition, Professor Vasso Apostolopoulos and Nobel Laureate Professor Harald zur Hausen received an award for career excellence by His Excellency, the President of the Hellenic Democracy, Mr. Prokopis Pavlopoulos. Last year, Professor John Matsoukas and Professor Vasso Apostolopoulos, were each independently awarded the Salus Index Award, from New Times Publishing, for outstanding career achievements, including their work on MS. The development of drugs, immunotherapeutics and vaccines against diseases is a long process, often taking researchers a lifetime. Researchers often work in silos, limiting their research output; as such, the breaking down of silos would improve research outcomes. Here, we provided an insight of a multi-institutional and multidisciplinary consortium which was developed over 20 years ago that has led to the identification and development of over 10 candidate immunotherapeutics against MS. Today, most research-funding bodies, require multi-institutional and multidisciplinary teams in order to be successful in grant applications. Most importantly, alliances are required to get to the target of the research. The authors declare no conflict of interest. Support for Greece Syriza May Have Lost the Election, but Greece's Research Reforms Deserve to Stay Treatment of experimental allergic encephalomyelitis (EAE) by a rationally designed cyclic analogue of myelin basic protein (MBP) epitope 72-85 Treatment of experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein epitope 72-85 with a Human MBP 87-99 analogue and effects of cyclic peptides Design and Synthesis of a Potent Cyclic Analogue of the Myelin Basic Protein Epitope MBP72-85: Importance of the Ala81Carboxyl Group and of a Cyclic Conformation for Induction of Experimental Allergic Encephalomyelitis Design and synthesis of small semi-mimetic peptides with immunomodulatory activity based on Myelin Basic Protein (MBP) Peptide 53-78 of myelin P2 protein is a T cell epitope for the induction of experimental autoimmune neuritis Induction of severe experimental autoimmune neuritis with a synthetic peptide corresponding to the 53-78 amino acid sequence of the myelin P2 protein Myelin Basic Protein Peptides: Induction and Inhibition of Experimental Allergic Encephalomyelitis Multiple Sclerosis: Immunopathology and Treatment Update Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82-98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis Conformational studies of immunodominant myelin basic protein 1-11 analogues using NMR and molecular modeling Design And Synthesis of a Novel Potent Myelin Basic Protein Epitope 87−99 Cyclic Analogue: Enhanced Stability and Biological Properties of Mimics Render Them a Potentially New Class of Immunomodulators † Designing peptide mimetics for the treatment of multiple sclerosis Conjugation of a peptide to mannan and its confirmation by tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis Peptide Ligands in Experimental Allergic Encephalomyelitis and Human T-Cell Proliferation Synthesis and study of the electrophoretic behavior of mannan conjugates with cyclic peptide analogue of myelin basic protein using lysine-glycine linker Structure and Function of the Myelin Proteins: Current Status and Perspectives in Relation to Multiple Sclerosis Citrullination of Linear and Cyclic Altered Peptide Ligands from Myelin Basic Protein (MBP87−99) Epitope Elicits a Th1 Polarized Response by T Cells Isolated from Multiple Sclerosis Patients: Implications in Triggering Disease Design of Novel Cyclic Altered Peptide Ligands of Myelin Basic Protein MBP83−99That Modulate Immune Responses in SJL/J Mice Towards immunotherapeutic drugs and vaccines against multiple sclerosis Round and round we go: Cyclic peptides in disease A double mutation of MBP83-99 peptide induces IL-4 responses and antagonizes IFN-? 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