Efeito imunomodulador das células mesenquimais do estroma em células T na artrite reumatóide

Mestrado em Biotecnologia - Biotecnologia MolecularA artrite reumatóide (AR) é uma doença inflamatória, crónica e sistémica que se caracteriza pela formação do pannus, tecido inflamatório neoformado com acumulação de células T auto-reativas. Estas células T são responsáveis pelo processo inflamatório através da libertação de citocinas e pela ativação de outras células, como macrófagos e fibroblastos sinoviais (principais produtores de citocinas pró-inflamatórias). Esta doença tem sido controlada por tratamentos com fármacos anti-reumáticos modificadores da doença que bloqueiam as citocinas inflamatórias, mas mais de 1/3 dos pacientes não respondem aos tratamentos. Assim uma das possíveis formas de tratamento que começa a ser explorada é o uso de células mesenquimais do estroma (MSC). As MSC são células progenitoras adultas, clonogénicas, não hematopoiéticas e multipotentes, com capacidade de auto-renovação e diferenciação em diversas linhagens celulares, que têm um efeito imunomodulador sobre as células T, inibindo a sua citotoxicidade e promovendo a produção de citocinas anti-inflamatórias, decrescendo a produção de citocinas pró-inflamatórias. Assim, este estudo pretende, com a realização de co-culturas entre MSC e células mononucleares, perceber qual o efeito das MSCs em doentes com AR e desta forma encontrar um caminho promissor para o tratamento desta doença autoimune. Os resultados mais relevantes foram a inibição da frequência de células T CD4+ e CD8+ produtoras de citocinas pró-inflamatórias como, IL-2, IFN-γ, TNF-α, IL-6, IL-17 e IL-9, em todos os compartimentos funcionais, em doentes com AR.Rheumatoid arthritis (RA) is an inflammatory, chronic and systemic disease which is characterized by the formation of pannus, inflammatory tissue neoformed with the amassing of self-reactive T cells. These T cells are responsible for the inflammatory process through the release of cytokines and the activation of other cells, such as macrophages and synovial fibroblasts (the main producers of pro-inflammatory cytokines). This disease has been controlled by treatment with disease-modifying anti-rheumatic drugs that block the inflammatory cytokines, its effectiveness shows that more than 1/3 of patients do not respond to the treatments. Considering that, one of the possible forms of treatment recently explored, is the use of mesenchymal stromal cells (MSC). The MSC are adult stem cells with clonogenic capacity, non-hematopoietic and multipotent, with the ability of self-renewal and differentiation into multiple cell lines, which have an immunomodulatory effect on T cells, inhibiting their cytotoxicity and promoting the production of anti-inflammatory cytokines, decreasing the production of pro-inflammatory cytokines. In conclusion, this study intends to understand the effect of MSCs in patients with RA, by performing co-cultures with MSC and peripheral blood mononuclear cells, aiming to the promising possibility that is the treatment of this autoimmune disease. The most relevant results were the inhibition of the frequency of CD4+ and CD8+ T cells which produces pro-inflammatory cytokines such as IL-2, IFN-γ, TNF-α, IL-6, IL-17 and IL-9, in all the functional compartments in patients with RA

Human Bone Marrow Mesenchymal Stromal/Stem Cells Regulate the Proinflammatory Response of Monocytes and Myeloid Dendritic Cells from Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human bone marrow (BM)-MSCs on myeloid dendritic cells (mDCs) and monocytes, especially on cytokines/chemokines involved in RA physiopathology. For that, LPS plus IFNγ-stimulated peripheral blood mononuclear cells from RA patients (n = 12) and healthy individuals (n = 6) were co-cultured with allogeneic BM-MSCs. TNF-α, CD83, CCR7 and MIP-1β protein levels were assessed in mDCs, classical, intermediate, and non-classical monocytes. mRNA expression of other cytokines/chemokines was also evaluated. BM-MSCs effectively reduced TNF-α, CD83, CCR7 and MIP-1β protein levels in mDCs and all monocyte subsets, in RA patients. The inhibition of TNF-α production was mainly achieved by the reduction of the percentage of cellsproducing this cytokine. BM-MSCs exhibited a remarkable suppressive action over antigen-presenting cells from RA patients, potentially affecting their ability to stimulate the immune adaptive response at different levels, by hampering their migration to the lymph node and the production of proinflammatory cytokines and chemokines. Accordingly, MSC-based therapies can be a valuable approach for RA treatment, especially for non-responder patients