Résumé
Multipotent mesenchymal stromal cells (MSC) are adult stem cells characterized by their differentiation potential into multiple lineages and their immunosuppressive properties. This last property is used here to evaluate the efficacy of primary MSC to inhibit inflammation-associated symptoms in the murine experimental model of collagen-induced arthritis (CIA). The role of iNOS and IL-6 in the suppressive activity of MSC is investigated. Methods. MSC were isolated from DBA1 and wild type (wt), inducible nitric oxid synthase (iNOS)-/- or IL-6-/-C57B16 mice. Cells were immunophenotyped and functionally tested. In the tumour model, MSC were subcutaneously co-injected with the B16 melanoma cells (10 super(5) of each cell type) in BALB/c mice. In CIA, 10 super(6) MSC were intravenously injected at various times after collagen II immunization of DBA1 mice. Arthritis was evaluated by the measure of paw swelling and immunological parameters. Results. All primary MSC populations were characterized by their common phenotype (CD45-, CD11b-, CD44+, CD73+, Sca1+) and differentiation potential towards chon-drocytes, adipocytes, osteoblasts. However, compared to wt MSC, iNOS-/- or IL-6-/- exhibited a highly reduced immunosuppressive effect. Using the B16 model, tumours develop in 80% of mice when wt MSCs were coinjected compared to 20 or 40% respectively, with iNOS-/- or IL-6-/-MSC. In the CIA model, when injected on day 18 and 24, syngeneic and allogeneic MSC were able to significantly decrease the incidence and clinical signs of arthritis. The immunological parameters confirmed a decreased inflammatory response with MSC. When iNOS-/- MSC were injected, the mean paw swelling did not significantly differ from that measured with wt MSC but the clinical score was dramatically and significantly increased. No significant differences were observed between IL-6--/-- or wt MSC. Conclusion. This study shows the efficacy of systemic injection of syngeneic or allogeneic MSC in the treatment of experimental arthritis in a restricted window of application. The role of iNOS in suppressing the inflammatory response in CIA is demonstrated whereas involvement of IL-6 is still under debate.