Análise comparativa do tratamento com fingolimode e dimetilfumarato na composição de linfócitos B, monócitos e diferentes subtipos de células T em pacientes com Esclerose Multipla

Abstract

Recurrent remitting multiple sclerosis (RRMS) is a chronic inflammatory autoimmune disease of the central nervous system considered to be the main cause, among demyelinating diseases, of chronic neurological disability in young adults. The rapid diagnosis and treatment with disease-modifying therapies (TMD), such as fingolimod (FGL) and dimethylfumarate (DMF), can alter the clinical course by controlling, through different mechanisms, immune events mediated by encephalitogenic T cells associated with relapses and neuronal injury. However, studies comparing the effects of both drugs on the composition of different T cell subsets, B cells and circulating monocytes are lacking, which is the objective of the present study. Thus, the total lymphocytes were stimulated for 3 h with the combination of PMA and ionomycin and subsequently labeled using different fluoroclaved monoclonal antibodies directed against the CD3, CD4, CD8, CD45RA, CCR7, IFN-γ, CD19, HLA-DR, CD28, CD57, CD14, CD80, CD86 and CD11c markers. For comparison, peripheral blood samples were collected from healthy individuals (control group) and from HIV-1 infected patients with AIDS. The determination of different cell subpopulations was carried out by flow cytometry. Our results demonstrate that treatment with FGL was more efficient in reducing both the total CD4+ T cells and the central memory cell subset. In the CD8+ T cell compartment, similar results were observed in patients with FGL therapy. The frequency of IFN- y+ (CD4+ and CD8+) T cells was higher in untreated MS patients than in the control group, and, among TMD, only FGL was capable in reducing the proportion of virgin IFN-y+CD8+T cells, associated with an increase in the frequency of circulating CD28-CD57-(CD4+ and CD8+) T cells. Inability of DMF of reducing circulating levels of virgin IFN-y+ T cells was directly associated with the degree of motor impairment of the patient. Different from DMF, FGL was able to elevate the proportions of monocytes (CD14+ HLA-DR+) and B lymphocytes (CD19+ HLA-DR+) expressing the activation markers CD80 and CD11c, respectively. Finally, and interestingly, although FGL leads to more pronounced lymphopenia in circulating central memory T cells in patients with MS compared to AIDS patients, an increase in the proportion of CD28-CD57- T cells and activated monocytes (CD80+CD86-) should contribute to immune resistance to different pathogens in patients with MS. Although preliminary, our data suggest that higher therapeutic efficiency in MS depends on the ability of TDM to reduce the frequency of virgin T IFN-y+ cells. In addition, although FGL leads to an important reduction in noble circulating T cell subtypes, it is possible that, by compensatory immune mechanisms, the great majory of these patients are able to maintain immune surveillance against different pathogens.