The online version of this article has a Supplementary Appendix. BackgroundMultipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo. Design and MethodsWe examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major ]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients. ResultsDespite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graftversus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-g, an important mediator of graft-versus-host disease. ConclusionsMesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-g. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells' effectiveness in attenuating graft-versus-host disease.Key words: stem cell transplantation, graft-versus-host disease, mesenchymal stromal cells, IFNg.Citation: Christensen ME, Turner BE, Sinfield LL, Kollar K, Cullup H, Waterhouse NJ, Hart DNJ, Atkinson K, and Rice AM. Mesenchymal stromal cells transiently alter the inflammatory milieu posttransplant to delay graft-versus-host disease. Haematologica 2010;95(12):2102-2110. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

Delineating the mechanisms underlying delayed onset GVHD in RIC HSCT recipients is vital to improve the prediction of disease onset and allow more targeted interventions for acute GVHD.