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Multiple Sclerosis: clinical study, neuropsicological, immunological, biomarker and disease modifying drugs

Grant number: 20/02048-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2020
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Leonilda Maria Barbosa dos Santos
Grantee:Fernando Pradella
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:14/26431-0 - Multiple sclerosis, clinical study, neuropsychological, immunological, biomarkers and modifying-disease new drugs, AP.TEM
Associated scholarship(s):23/09781-7 - Effect of the microRNA-92a loss on CD8+ T cells and B cells in mice with EAE and Multiple Sclerosis patients, BE.EP.PD


Multiple Sclerosis (MS) is an autoimmune disease of the Central Nervous System (CNS) characterized by inflammation and neurodegeneration. Inflammation can be initiated by transmigration of autoreactive T lymphocytes and other leukocytes through the Blood-Brain Barrier (BBB), resulting in demyelination, degeneration and axonal damage to the white and gray matter of the CNS; 1) MS usually affects young adults aged between 20 and 40 years; women are affected at least twice as often as men, and the diagnosis of depression associated with the development of multiple sclerosis is not uncommon. The afferent phase of CNS immunity involves the transport of neuroantigens by Dendritic Cells (DCs) to secondary lymph nodes, where naive T cells will be initiated by autoantigens, generating central memory T cells that circulate through the bloodstream and other organs. lymphoids and culminates in the efferent phase of the immune response, leading to tissue damage; 2) the trafficking of autoreactive lymphocytes through the blood-brain barrier of patients with MS in the efferent phase of the immune response is mediated by the increased surface expression of integrin molecules, such as integrins alpha-4 beta-1 (±4²1). Based on this mechanism, the humanized anti-±4 monoclonal antibody, called Natalizumab (NTZ), was developed to inhibit the migration of autoreactive T cells to the CNS, blocking the function of integrin; 3) in addition to its mode of action of blocking adhesion , NTZ was appears to modulate the immune system; 4) DCs comprise plasmacytoid DCs (pDCs) and conventional DCs, of myeloid origin. Depending on the inflammatory context, the presentation of autoantigens mediated by dendritic cells can promote or inhibit an autoimmune response; 5) our group has previously demonstrated the immunomodulatory effect of pDCs before verifying that the in vivo administration of CpG-ODN, an agonist of TLR9 and TLR7, stimulated the production of indoleamine 2,3 dioxigenase (IDO) by pDCs, essential for the generation of cells Adaptive regulatory T induced by human plasmacytoid dendritic cells, significantly reducing the severity of EAE; 6) in this study, we will evaluate the effect of NTZ treatment on the expression of immunomodulatory molecules on the surface of conventional myeloid and plasmacytoid DCs in peripheral blood, such as HLA-DR, HLA-G, PD-L1 and CCR7. The neurofilament light chain (Nfl) is the light subunit of neuron triplet proteins, which is a minor cytoskeletal constituent of the neuronal cell body and dendrites; 7) to assess the anti-inflammatory function of these molecules in the CNS with neurodegeneration, we will quantify the chain Nfl in the CSF of patients treated with NTZ. Thus, an increase in the concentration of the Nfl chain in the CSF may indicate axonal damage and a reduction may indicate neuroprotection. (AU)

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