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A1.10 Human bone marrow-derived mesenchymal stromal cells strongly inhibit cytokine production by naive, memory and effector CD4+ and CD8+ T cells from rheumatoid arthritis patients, independently of disease activity status
  1. M Pedrosa1,2,
  2. C Duarte3,
  3. P Laranjeira1,
  4. J Gomes1,4,
  5. T Ribeiro5,
  6. F Santos5,
  7. B Antunes5,
  8. S Pedreiro1,
  9. A Henriques1,6,
  10. A Martinho1,
  11. M Fardilha2,
  12. H Trindade1,
  13. JA da Silva3,
  14. A Paiva1
  1. 1Portuguese Institute for Blood and Transplantation, Quinta Da Vinha Moura, São Martinho Do Bispo, Coimbra, Portugal
  2. 2Signal Transduction Laboratory, Center of Cellular Biology, SACS and Departament of Biology, University of Aveiro, Aveiro, Portugal
  3. 3Rheumatology Department of University Hospital Center of Coimbra, Praceta Professor Mota Pinto, Coimbra, Portugal
  4. 4QOPNA, Department of Chemistry, University of Aveiro, Aveiro, Portugal
  5. 5Cell2B Advanced Therapeutics, SA, Biocant Park, Núcleo 04, Cantanhede, Portugal
  6. 6Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal

Abstract

Background and objectives Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by autoimmune activation leading to local and systemic consequences. Self-reactive T cells play a decisive role in the initiation and maintenance of the disease process.

This disease course has been deeply modified by disease-modifying anti-rheumatic drugs that block pro-inflammatory cytokines, but still more than 1/3 of patients do not respond adequately to treatment. To overcome this limitation, mesenchymal stromal cells (MSC) based therapies have been recently explored.

MSC are a population of adult non-hematopoietic stem cells with the ability to immunomodulate different cells of the immune system.

The aim of this study was to verify the immunomodulatory activity of bone marrow (BM)-derived MSC on peripheral blood helper (Th) and cytotoxic T cells (Tc), distributed among their different functional compartments (naïve, central memory, effector memory and effector) from RA patients and healthy individuals.

Materials and methods To this purpose we preformed co-cultures with mononuclear cells and BM-MSC from 12 RA patients and 8 controls during 20 h in a ratio of 2:1 (MNC:BM-MSC). Then, T cells were activated with PMA and ionomycin for 4 h to induce cytokine production by T cells. The frequency of Th and Tc cells producing cytokines (IL-2, IFN-γ, TNF-α, IL-6, IL-17 and IL-9) among the different functional compartments was measured by flow cytometry. Moreover, IL-4, IL-10, TGF-β and CTLA-4 mRNA expression was assessed after cell sorting of CD4+ and CD8+ T cells.

Results BM-MSC clearly induced a decrease in the frequency of CD4+ and CD8+ T cells producing pro-inflammatory cytokines (for all the cytokines analysed) in all functional compartments and in both groups under study. However, the intensity of inhibition varied with the cytokine and the T cell functional compartment. Regarding the mRNA expression, in the presence of BM-MSC, we observed an increase of IL-4, IL-10, TGF-β and CTLA-4 in purified CD4+ T cells for both groups, although in a lower extent in RA patients. Likewise, BM-MSC induced an augment of mRNA levels of the abovementioned molecules in CD8+ T cells, although a more pronounced mRNA expression was observed in RA patients, excepting for IL-4, which expression decreased in both groups.

Conclusions Our data show that BM-MSC effectively inhibit pro-inflammatory cytokines production by Th and Tc in all functional compartments and increase the mRNA expression of anti-inflammatory molecules in both T cell subpopulations. These results support their potential utility in the treatment of autoimmune diseases.

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