Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.
OBJECTIVE
Adult mesenchymal stem cells (MSCs) represent promising tools for therapeutic applications such as tissue engineering and cellular therapy. Recent data suggest that, due to their immunosuppressive nature, MSCs may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease. Using a murine model of rheumatoid arthritis (RA), this study investigated whether the immunosuppressive properties of MSCs could be of therapeutic value to inhibit reactive T cells in autoimmune diseases such as RA.


METHODS
In mice with collagen-induced arthritis (CIA), we injected various doses of C3 MSCs at the time of immunization or booster injection, and subsequently evaluated the clinical and immunologic parameters. The immunosuppressive properties of MSCs were determined in vitro in mixed lymphocyte reactions with or without the addition of tumor necrosis factor alpha (TNFalpha).


RESULTS
In the CIA model of arthritis, MSCs did not confer any benefit. Both the clinical and the immunologic findings suggested that MSCs were associated with accentuation of the Th1 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 the addition of TNFalpha was sufficient to reverse the immunosuppressive effect of MSCs on T cell proliferation, and this observation was associated with an increase in interleukin-6 secretion.


CONCLUSIONS
Our data suggest that environmental parameters, in particular those related to inflammation, may influence the immunosuppressive properties of MSCs.
Djouad
Farida
F
INSERM U475, Montpellier, France.
Fritz
Vanessa
V
Apparailly
Florence
F
Louis-Plence
Pascale
P
Bony
Claire
C
Sany
Jacques
J
Jorgensen
Christian
C
Noël
Danièle
D
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D003094:Collagen / Q000008:administration & dosage; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003094:Collagen