Tumor necrosis factor alpha reverses the immunosuppressive properties of mesenchymal stem cells in collagen-induced arthritis
© BioMed Central Ltd 2005
Received: 11 January 2005
Published: 17 February 2005
Mesenchymal stem cells (MSCs) are bone-marrow-derived progenitor cells, widely investigated for their potential of differentiation towards multiple lineages, such as osteocytes and chondrocytes. Recently, we and others showed that MSCs exhibit immunosuppressive properties inducing in vivo tolerance of T lymphocytes towards allogeneic cells. Moreover, these cells can be easily genetically modified to express ectopic molecules, such as anti-inflammatory cytokines.
Here, we investigated whether naïve and IL-10-expressing MSCs could display an inhibitory effect towards self-reactive T lymphocytes in vitro and have a biological effect in the murine model of collagen-induced arthritis (CIA).
We used the murine C3H10T1/2 cell line (C3 MSCs) in the CIA murine model of RA. We injected various doses of MSC at immunization or at boost and evaluated the clinical and immunological parameters. Immunosuppressive properties of MSC were determined in vitro in mixed lymphocyte reactions.
We evaluated the potential immunosuppressive role of MSCs in the CIA model and showed that MSCs did not display any benefit whatever the day of cell injection (day 0 or day 21) and the numbers of MSCs (106 or 4 × 106). Both clinical and immunological analysis argued for the accentuation of the Th1 helper response. Using luciferase-expressing MSCs, we were unable to detect labeled cells in the articular environment of the knee, suggesting that worsening of the symptoms was unlikely due to the homing of MSCs in the joints. Experiments in vitro showed that addition of tumor necrosis factor alpha was sufficient to reverse the immunosuppressive effect of MSCs on T-cell proliferation and this observation was associated with an increase of IL-6 secretion.
Here, we demonstrated that the immunosuppressive properties of MSCs did not provide any clinical benefit in CIA. Our data suggest that environmental parameters, in particular inflammation, may influence the immunosuppressive properties of MSCs.