Oportunidades de Dissertação Antigas

Instituição: ICVS – Escola de Medicina, Universidade do Minho

Nome do Responsável: Cláudia Nobrega

Contacto: claudianobrega@med.uminho.pt

Área de atuação: Neuroimunologia

Tema da Dissertação: Inflammation at the nervous system interfaces

Descrição da Dissertação: Multiple sclerosis (MS) is a highly debilitating autoimmune disease of the central nervous system that affects more than 2.3 million people worldwide, and over 5000 in Portugal. This autoimmune disease is mediated to a great extent by autoreactive T cells. The initial course of MS follows one of two paths: the relapse-remitting (RRMS) and the primary progressive (PPMS), the former representing 85-90% of total MS cases. The natural progression of MS increases treatment-related costs and impacts highly on patient’s wellbeing which highlights the urgency to find a cure or treatment to halt disease progression (1). Autologous hematopoietic stem cell transplantation (aHSCT), devoted to the most severe forms of disease, leads to a relevant delay of disease progression and, in 3 out of 10 patients, to suppression of disease manifestation assessed 10 years following aHSCT (2). These trials’ success suggests that newly differentiated T cells, generated by the patient thymus, do not directly drive MS. Two main exciting hypotheses need to be tested: are the circumstances that lead to the differentiation and activation of autoreactive T cells transitory (ie. happening before disease onset), and/or rely on a slow and progressive process that takes several years to manifest. Addressing these hypotheses is the main goal of this proposal. To tackle these issues, the project is based on a cohort of newly-diagnosed RRMS and PPMS patients, and healthy controls (HC). Studying MS patients in such an initial phase of the disease manifestation is essential to identify immunological alterations, specifically at the T cells’ level, closer to the initial events that drive MS. In contrast to the reported prematurely aged immune system in MS patients (e.g. (3)) our results show that newly-diagnosed RRMS patients have lower overall percentages and numbers of memory CD4+ and CD8+ T cells, suggestive of general T cells alterations at disease onset (Annex1). To identify these modifications, we will first undertake an exploratory approach by evaluating the transcriptional profile of T cell subsets, at the single cell level. We will first focus on the most immature RTE, to the naïve and memory T cells, though we expect other T cell subsets to arise based on the transcriptome analysis. As blood T cells’ phenotype tips towards a less activated phenotype in newly-diagnosed MS patients, we will perform functional assays that will allow us to understand if, in these patients,: i) naïve T cells have impaired homeostatic proliferation [upon stimulation of CD31+ naïve T cells (RTE) with IL7]; ii) the T cell receptor activation threshold is altered thus impairing differentiation of naïve T cells into the memory phenotype; iii) memory T cells are less proliferative and/or more prone to die upon stimulation with specific (myelin peptides) or unspecific stimuli; iv) overall memory T cells are more prone to migrate to tissues. All these analyses will be performed in newly-diagnosed RRMS patients, and HC.

Período: a discutir com o candidato