Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Comprehensive Insight of the Immunosuppressive Effect of Mesenchymal Stem Cells in Arthritis
Bouffi1, Carine, Bony1, Claire, Courties1, Gabriel, Jorgensen2, Christian, Noel1, Danièle
Multipotent mesenchymal stromal cells (MSC) are adult stem cells characterized by their differentiation potential and their immunosuppressive properties. Among the proposed mediators of this immunomodulatory effect, IDO, iNOS, IL-6 and PGE2 were consistently reported to play a major role, at least in vitro. The aim of our study was to better understand the molecular mechanisms involved in the immunosuppressive effect of MSCs in vivo and relied on the murine experimental model of collagen-induced arthritis (CIA).
MSCs were isolated from DBA1 mice and wild type (wt), inducible nitric oxid synthase (iNOS)-/- or IL-6-/- C57Bl6 mice. Cells were immunophenotyped by flow cytometry. Their capacity to differentiate into 3 lineages was induced by culture in specific conditions and immunosuppression was evaluated in concanavalin A-induced proliferative assay. In vivo, 106 MSC were intravenously injected at various times after collagen II (bCII) immunization of DBA1 mice. Arthritis was evaluated by the measure of paw swelling and immunological parameters (collagen II-specific immunoglobulins, inflammatory cytokines and proliferation of T lymphocytes).
All primary MSC populations were characterized by their common phenotype, trilineage differentiation potential and immunosuppressive potential. Using a proliferative assay, iNOS-/- or IL-6-/- MSCs exhibited a highly reduced immunosuppressive effect compared to wt MSCs while IDO activity was totally absent in murine MSCs. These results were confirmed in vivo in the CIA model. When injected on day 18 and 24, syngeneic MSCs were able to significantly decrease the incidence and the clinical signs of arthritis. A similar beneficial effect was also observed when allogeneic wt C57Bl6 MSCs were injected. The immunological parameters (proliferative assay, bCII-specific IgG1/IgG2A, cytokine profile) confirmed a decreased inflammatory response when MSCs were administered. However, when iNOS-/- or IL-6-/- MSCs were injected, the therapeutic effects of MSCs were partially reversed. This suggests that NO, IL-6-induced PGE2 secretion or IL-6-dependent dendritic cell maturation play only minor roles as well as CD4+CD25+Foxp3+ T reg cells that were only slightly increased.
Our study shows the efficacy of systemic injection of syngeneic or allogeneic MSCs in the treatment of experimental arthritis in a restricted window of application. The mechanism of immunosuppression is complex and relies on more than one molecular pathway.
To cite this abstract, please use the following information:
Bouffi, Carine, Bony, Claire, Courties, Gabriel, Jorgensen, Christian, Noel, Danièle; Comprehensive Insight of the Immunosuppressive Effect of Mesenchymal Stem Cells in Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :16