Multiple sclerosis, clinical study, neuropsychological, immunological, biomarkers and modifying-disease new drugs

• Grant number: 14/26431-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: November 01, 2018
• End date: March 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Leonilda Maria Barbosa dos Santos
• Grantee: Leonilda Maria Barbosa dos Santos
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Benito Pereira Damasceno ; Elaine Conceicao de Oliveira
• Associated scholarship(s): 20/03558-6 - Lymphopenia in multiple Sclerosis patients treated with dimethyl fumarate: the role of IL-2 in proliferative response of lymphocytes, BP.IC; 20/02048-4 - Multiple Sclerosis: clinical study, neuropsicological, immunological, biomarker and disease modifying drugs, BP.PD; 19/18417-1 - Multiple sclerosis: clinical, immunological and neuropsiquiatric aspects biomarkers and drugs modifying of the disease, BP.IC; 19/02547-3 - Subpopulations of B-lymphocytes in patients with primária progressive Multiple Sclerosis in treatment with monoclonal antibody against CD20 (ocrelizumab), BP.DD

Abstract

Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system. This is a major socioeconomic problem, since MS affects mainly young adults (18-40 years), in the most productive phase of life.MS is caused by two mechanisms that overlap inflammation and neurodegeneration. Cortical atrophy, observed since the onset of the disease, may be responsible for the symptoms of the disease, including the cognitive and psychiatric disorders observed in patients. Available treatments, besides being costly, are only partially effective in alleviating inflammation, and do not change the natural course of the disease. New therapeutic strategies that aim to stimulate neuroprotection and slow or even stop neurodegeneration are therefore necessary. In this scenario, the identification of genetic and biological markers of neurodegeneration is essential in order to obtain possible therapeutic targets. In this proposal, we intend to study the immunological response of the patients in treatment with the new drugs modifying the disease, in order to acquire our experience with these treatments. Recent works show that the participation of B lymphocytes in the pathogenesis of MS has been neglected for years. Classical study using monoclonal antibodies for B lymphocyte depletion showed a beneficial effect in patients with the relapsing / remission form of the disease. Another generation of anti-B lymphocyte (humanized) antibody is entering the Brazilian market and recent studies show that B lymphocyte depletion may also benefit patients with the progressive form of the disease. Thus, an important approach of this proposal is to study the subpopulations of B lymphocytes (cytotoxic or suppressive) before the arrival of Ocrelizumab in Brazil, with the objective of identifying (if possible) the patients who will benefit with the monoclonal antibody treatment. The study of subpopulations of B lymphocytes is also the tonic in the groups of patients treated with other drugs like fingolimod and natalizumab. Dimethyl fumarate is another drug that is coming to Brazil for the treatment of MS. In this proposal it is our objective to study the effect of this treatment both in patients with MS and in the animal model of experimental autoimmune encephalomyelitis (EAE). The mechanisms of action of dimethyl fumarate are poorly understood. The Nrf2 pathway appears to be linked to neuroprotection, whereas stimulation of HCAR2 by monomethyl fumarate inhibits the production of anti-inflammatory cytokines. Thus, in this study we will mainly address the problem of DMF-induced lymphopenia and the effect of treatment in the intestinal mucosa. Recent studies show that treatment with DMF induces significant lymphopenia that even exposes patients to infection with JC Virus, which can be fatal. In this proposal, we will study mechanisms that lead to the reduction of the proliferative response of lymphocytes from individuals treated with DMF such as IL-2 production and apoptosis of activated human and murine T lymphocytes treated with DMF. This study may detect early individuals who will have severe lymphopenia and alert the clinician to the mechanisms that may lead to a marked decrease in lymphocytes during treatment. Biological markers will be identified in the kinurenin pathway through the use of mass spectrometry in both cerebrospinal fluid and serum of MS patients and these markers will be associate with depression observed in some MS patients. All patients will be submitted to magnetic resonance imaging and the clinical, cognitive and psychiatric aspects will be evaluated. Clinical findings will be compared to possible biological markers including quantification of neurofilament L. Recently the microbiome has been studied in MS, both in the sense of identifying bacteria involved in the genesis of the disease, as well as products of bacteria such as small fatty acids such as butyrate and probably monomethyl fumarate that stimulate HC. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MORAES, ADRIEL S.; BOLDRINI, VINICIUS O.; DIONETE, ALLINY C.; ANDRADE, MARILIA D.; LONGHINI, ANA LEDA F.; SANTOS, IRENE; LIMA, AMANDA D. R.; SILVA, VERONICA A. P. G.; DIAS CARNEIRO, RAFAEL P. C.; QUINTILIANO, RAPHAEL P. S.; et al. Decreased Neurofilament L Chain Levels in Cerebrospinal Fluid and Tolerogenic Plasmacytoid Dendritic Cells in Natalizumab-Treated Multiple Sclerosis Patients - Brief Research Report. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 15, JUL 26 2021. (12/09879-2, 14/26431-0, 13/00837-8)

BOLDRINI, VINICIUS O.; MARQUES, ANA M.; QUINTILIANO, RAPHAEL P. S.; MORAES, ADRIEL S.; STELLA, CARLA R. A. V.; LONGHINI, ANA LEDA F.; SANTOS, IRENE; ANDRADE, MARILIA; FERRARI, BRENO; DAMASCENO, ALFREDO; et al. ytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patient. FRONTIERS IN IMMUNOLOGY, v. 13, FEB 7 2022. (19/16116-4, 17/21363-5, 14/26431-0, 15/22052-8, 19/06372-3)

TAUIL, C. B.; ROCHA-LIMA, A. D.; FERRARI, B. B.; SILVA, F. M.; MACHADO, L. A.; RAMARI, C.; BRANDAO, C. O.; DOS SANTOS, L. M. B.; DOS SANTOS-NETO, L. L.. Depression and anxiety disorders in patients with multiple sclerosis: association with neurodegeneration and neurofilaments. Brazilian Journal of Medical and Biological Research, v. 54, n. 3, 2021. (14/26431-0, 16/17404-5)

BOLDRINI, VINICIUS O.; QUINTILIANO, RAPHAEL P. S.; SILVA, LUCAS S.; DAMASCENO, ALFREDO; SANTOS, LEONILDA M. B.; FARIAS, ALESSANDRO S.. Cytotoxic profile of CD3+CD20+T cells in progressive multiple sclerosis. MULTIPLE SCLEROSIS AND RELATED DISORDERS, v. 52, JUL 2021. (17/21363-5, 19/06372-3, 14/26431-0)

TAUIL, CARLOS B.; LIMA, AMANDA D. DA ROCHA; FERRARI, BRENO B.; DA SILVA, VERONICA A. G.; MORAES, ADRIEL S.; DA SILVA, FLAVIA M.; MELO-SILVA, CESAR A.; FARIAS, ALESSANDRO S.; BRANDA, CARLOS O.; LEONILDA, M. B. DOSSANTOS; et al. Depression and anxiety in patients with multiple sclerosis treated with interferon-beta or fingolimod: Role of indoleamine 2,3-dioxygenase and pro-inflammatory cytokines. BRAIN, BEHAVIOR, & IMMUNITY - HEALTH, v. 9, p. 7-pg., 2020-12-01. (14/26431-0, 16/17404-5)

LIMA, AMANDA D. R.; FERRARI, BRENO B.; PRADELLA, FERNANDO; CARVALHO, RODRIGO M.; RIVERO, SANDRA L. S.; QUINTILIANO, RAPHAEL P. S.; SOUZA, MATHEUS A.; BRUNETTI, NATALIA S.; MARQUES, ANA M.; SANTOS, IRENE P.; et al. Dimethyl fumarate modulates the regulatory T cell response in the mesenteric lymph nodes of mice with experimental autoimmune encephalomyelitis. FRONTIERS IN IMMUNOLOGY, v. 15, p. 10-pg., 2024-05-03. (18/03432-2, 14/26431-0)

BRASIL MATOS, ALINE DE MOURA; MAIA CARVALHO, FERNANDA MARTINS; MALTA, DANIELLE LIMA; RODRIGUES, CLEONISIO LEITE; FELIX, ALVINA CLARA; PANNUTI, CLAUDIO SERGIO; DA ROCHA LIMA, AMANDA DIAS; ALVES ESPOSITO, DANILO LUCAS; BARBOSA DOS SANTOS, LEONILDA MARIA; VON GLEHN, FELIPE; et al. High proportion of Guillain-Barre syndrome associated with chikungunya in Northeast Brazil. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION, v. 7, n. 5, p. 4-pg., 2020-09-01. (14/26431-0, 19/03859-9)