Novel Experimental Strategies to Treat Multiple Sclerosis

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Novel Experimental Strategies to Treat Multiple Sclerosis ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials dʼinvestigació i docència en els termes establerts a lʼart. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix lʼautorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No sʼautoritza la seva reproducció o altres formes dʼexplotació efectuades amb finalitats de lucre ni la seva comunicació pública des dʼun lloc aliè al servei TDX. Tampoc sʼautoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral. No se autoriza su reproducción u otras formas de explotación efectuadas con fines lucrativos ni su comunicación pública desde un sitio ajeno al servicio TDR. Tampoco se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al contenido de la tesis como a sus resúmenes e índices. WARNING. The access to the contents of this doctoral thesis and its use must respect the rights of the author. It can be used for reference or private study, as well as research and learning activities or materials in the terms established by the 32nd article of the Spanish Consolidated Copyright Act (RDL 1/1996). Express and previous authorization of the author is required for any other uses. In any case, when using its content, full name of the author and title of the thesis must be clearly indicated. Reproduction or other forms of for profit use or public communication from outside TDX service is not allowed. Presentation of its content in a window or frame external to TDX (framing) is not authorized either. These rights affect both the content of the thesis and its abstracts and indexes. NOVEL EXPERIMENTAL STRATEGIES TO TREAT MULTIPLE SCLEROSIS Presented by Alba Sánchez Fernández ACADEMIC DISSERTATION To obtain the degree of PhD in Neuroscience by the Universitat Autònoma de Barcelona (2019) NOVEL EXPERIMENTAL STRATEGIES TO TREAT MULTIPLE SCLEROSIS Presented by Alba Sánchez Fernández ACADEMIC DISSERTATION To obtain the degree of PhD in Neuroscience by the Universitat Autònoma de Barcelona (2019) Directed by: Tutorized by: Rubèn López Vales Xavier Navarro Acebes INDEX Summary.............................................................................................................................. 4 Introduction ....................................................................................................................... 5 1. Multiple sclerosis ............................................................................................... 5 2. The inflammatory response in Multiple Sclerosis ................................ 12 3. Animal models of Multiple Sclerosis .......................................................... 16 4. Current therapies for Multiple Sclerosis ................................................... 19 5. Interleukin-1 Family ........................................................................................ 22 6. Resolving the inflammation ........................................................................... 30 Objectives ............................................................................................................................ 44 Materials and methods ................................................................................................... 46 - Human samples ......................................................................................................... 46 - Mice ................................................................................................................................ 47 - Experimental Autoimmune Encephalomyelitis induction ........................ 48 - Experimental Autoimmune Encephalomyelitis evaluation ...................... 48 - Drug administration ................................................................................................ 49 - Real-time quantitative PCR ................................................................................... 50 - Histological analysis ................................................................................................ 51 - Cytokine protein expression assessment ........................................................ 52 - Fluorescence activated cell sorting ................................................................... 52 - Statistical analysis .................................................................................................... 55 Results .................................................................................................................................. - Chapter 1. OLT1177 ................................................................................................. 57 - Chapter 2. IL-37 ......................................................................................................... 81 - Chapter 3. Maresin-1 ............................................................................................... 109 General discussion ........................................................................................................... 131 Conclusions ......................................................................................................................... 142 References ........................................................................................................................... 144 Abbreviations .................................................................................................................... 162 SUMMARY Despite multiple sclerosis was described by Dr. Jean-Martin Charcot in the 19th century, it is currently a challenging neurological disorder. The etiology of this pathology is not fully understood but the degeneration that occurs in myelin sheaths and neurons in individual suffering from multiple sclerosis is linked to aberrant presence of immune cells in the lesioned central nervous system. For this reason, in the present thesis we propose to modulate the inflammatory response to ameliorate neurological decline and demyelination in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. The data shown here reveals that the administration of anti-inflammatory approaches, such as OLT1177 and IL-37, or specialized pro-resolving mediators, such as Resolvin-D1 or Maresin-1, has therapeutic effects in mice with experimental autoimmune encephalomyelitis, even if these treatments are initiated at the onset of the disease. OLT1177, IL-37 and Maresin-1 exerts beneficial effects by reducing some common aspects of inflammation, such as the production pro-inflammatory cytokines and the accumulation of immune cells. IL-37 and Maresin-1 also modulate the inflammatory response in the periphery and alter the polarization of lymphocyte and macrophage towards a more anti-inflammatory or regulatory phenotype. Collectively, the results presented here provide novel data that could pave the way to develop more effective strategies to treat multiple sclerosis. INTRODUCTION 1. MULTIPLE SCLEROSIS More than 100 years has passed since Charcot, Carswell, Cruveilhier and others described the clinical and pathological characteristics of multiple sclerosis (MS). This disease has originally been defined as a chronic inflammatory disease of the central nervous system (CNS), leading to focal plaques of primary demyelination and axonal damage in the white matter of the brain and spinal cord. It manifests clinically as neurological deficit (Charcot, 1880). 40 years later it was categorized as an autoimmune disease (Wu and Alvarez, 2011; Baecher-Allan et al., 2018). However, the aetiology and the pathogenesis of this disease are not yet conclusively known (Reviewed at Dyment et al., 2004; Trapp and Nave, 2008; Wu and Alvarez, 2011; Tselis, 2012; Didonna and Oksenberg, 2017; Baecher-Allan et al., 2018). This enigmatic, relapsing and often eventually progressive disorder of the white matter of the CNS continues to challenge researchers trying to understand the pathogenesis of the disease and prevent its progression. MS is a chronic, slowly progressive, inflammatory, demyelinating and degenerative disease of the CNS characterized by an autoimmune inflammation(Malpass, 2012; Grigoriadis and van Pesch, 2015; Bjelobaba et al., 2017). The symptoms vary widely, and affected individuals can experience one or more effects of nervous system damage This pathology affects about 2.5 million people worldwide, ranking as one of the most prevalent neurodegenerative diseases (Wekerle, 2008). MS affects 50000 people in
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