Session Type: Abstract Submissions (ACR)
Background/Purpose: Mesenchymal stem cells (MSCs) are multipotent cells with capacity to differentiate into osteoblasts, chondrocytes, and adipocytes. A phase II study in Europe has shown intravenous infusion of ex vivoexpanded MSCs might be an effective treatment for steroid-resistant, acute graft-versus-host disease. This result raised the question of whether a similar therapy would be beneficial for autoimmune diseases. Although some studies have shown that MSCs can suppress T cell proliferation, the mechanism (s) by which MSCs suppress T cell function are not well understood. Also, whether the immunosuppressive functions of MSCs are unique to MSCs or a more general function of stromal cells has been questioned. The purpose of this study is to compare the suppressive effect of MSCs from different sources and skin fibroblasts (FB) on T cell activation, proliferation and differentiation, and to examine whether the underlying mechanisms by which suppression occurs are similar.
Methods: Purified mouse TCRβ+ CD44- CD62Lhigh näive T cells were activated with anti-CD3/anti-CD28 antibodies, either alone or in transwell contact-independent co-cultured with human adipose derived stem cells (ADSC), human bone marrow stromal cells (BMSC), human fibroblasts (FB), human umbilical vein endothelial cells (HUVEC). T cell activation and proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester (CFSE) and FlowJo software. T cell surface markers, intracellular cytokine expression, MSCs and FB surface markers were analyzed by flow cytometry.
Results: ADSC and BMSC, but not FB, demonstrate trilineage differentiation potentials. After three days of co-culture of naïve T cells with ADSC, BMSC, FB or HUVEC, proliferation analysis showed that the percentage of divided cells (division index) was lower in ADSC, BMSC, FB groups compared to T-cell-only group and HUVEC group. However, after T cells had divided at least once, no difference in the further cell division (proliferation index) was observed. This indicates that ADSC, BMSC and FB suppress either activation or commitment to enter the cell cycle, rather than proliferation of activated T cells. Stromal cells needed to be present during the first 24 hours of T cell activation, and could not suppress T cell proliferation when added after that. By using sorted Foxp3–T cells, the suppressive effect of stromal cells on T cell proliferation was shown to be independent of Treg. Analysis of naïve CD8 T cells showed similar results. L-NAME, an inhibitor of inducible nitric oxide synthetase (iNOS) reversed the suppressive effects of BMSC, ADSC and FB at a concentration of 50µM.
Conclusion: Mesenchymal stem cells (ADSC and BMSC) and fibroblasts can suppress T cell activation independent of Treg at a stage prior to the first cell division. This suppression can be reversed by inhibition of iNOS. These results indicate that immunomodulatory function is not unique to MSCs, and may be unrelated to their “stemness”. Stromal cells with different tissue origins such as skin-derived fibroblasts probably share similar properties.
R. M. Siegel,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mesenchymal-stem-cells-and-skin-fibroblasts-both-suppress-early-steps-in-t-cell-activation-in-a-nitric-oxide-dependent-manner/