IL10-Transduced Mesenchymal Stem Cells Attenuate Experimental Acute Graft-Versus-Host Disease.

Recent data suggest that, due to their immunosuppressive nature, adult mesenchymal stem cells (MSCs) may be of interest to enhance allogeneic hematopoietic engraftment and prevent graft-versus-host disease (GVHD).

Using a murine model of acute GVHD, this study investigated whether the immunosuppressive properties of MSCs could reduce the severity of experimental GVHD. In a MHC-mismatched C57BL/6→B6D2F1 model, recipient animals were transplanted with bone marrow (BM) cells (10x10⁶) plus 20x10⁶ splenocytes after 1100 cGy on day 0. Various doses (1~3x10⁶) of donor BM-derived MSCs were given intravenously from day 1 to day 5 and subsequently evaluated the clinical and immunologic parameters.

MSCs did not attenuate the severity of acute GVHD. Using GFP expressing MSCs, we were unable to detect labeled cells in liver, spleen, lymph nodes and lung day 7 post-BMT. Because MSCs fail to display any immunosuppression in this experimental GVHD model and induce an immunosuppressive microenvironment through the production of IL10, we investigated whether the use of genetically modified MSCs expressing IL10 (IL10-transduced MSCs, IL10 MSCs) could improve the GVHD protection. Lethally irradiated recipients were transplanted and injected with 2x10⁶ IL10 MSCs, MSC expressing MIG as a vector (MIG MSCs), or diluent on day 1. Compared with MIG MSCs or controls, recipients of IL10 MSCs demonstrated significantly reduced mortality at day 50 after BMT (percent survival, 0% or 10% vs 70%, P<0.001). The reduction in mortality was confirmed by the semi-quantitative GVHD score (P<0.01). It was associated with decreased serum levels of pro-inflammatory cytokines, IFN_γ on day 7 (IL10 MSCs vs MIG MSCs; 297±116 pg/ml vs 681±87 pg/ml, P=0.015). Serum levels of TNF_α or splenic donor CD3+ cell numbers were not different between the groups. Thus, benefical effects on GVHD could be observed when MSCs were engineered to express an anti-inflammatory cytokine, IL10. The mechanisms for the GVHD protection effect of IL10 MSCs in this murine model are currently under investigation.