A Comparison of Mesenchymal Cells from Different Tissues To Suppress T-Cell Activation.

Abstract

Graft failure and graft-versus-host-disease (GvHD) remain significant complications of allogeneic stem cell transplantations. To reduce the risk of GvHD, patients often receive a graft that has been depleted of T-cells, which in turn increase the risk of graft failure. Studies have suggested that co-transplantation of ex vivo expanded marrow derived mesenchymal stem cells (MSCs) with allogeneic hematopoietic stem cells (HSC) reduces the risk of GvHD and graft rejection. Additionally, it has been shown that infusion of expanded marrow derived MSCs improves ongoing acute GvHD and facilitates engraftment across MHC-barriers. The effect of MSCs is thought to be due to their ability to suppress T-cell activation. Here we wished to examine whether inhibition of T-cells could be enhanced by MSCs from different tissues. We were particularly interested in MSCs derived from adipose tissue, because of its abundance and accessibility, which is especially important for repeat applications. We investigated and compared the immunosuppressive potential of MSCs derived from multiple mesenchymal tissues of different origins, such as adipose tissue, muscle tissue, omentum, and bone. Cells from the different tissues were enriched for MSCs and cultured and expanded for two to three weeks to deplete hematopoietic cells. MSCs from all tissues differentiated into multiple lineages and stained positive using antibodies against common MSC markers (CD29, CD44, CD105, CD106) and negative for hematopoietic markers (CD3, CD14, CD34, CD45). Mixed lymphocyte reactions (MLRs) using either a mitogen (Concanavalin A) or allogeneic T-cells as inducers of T-cell activation were performed in the presence or absence of MSCs from the different tissues. Mitogen-induced T-cell activation, as well as allogeneic T-cell responses were significantly reduced in MLRs with MSCs compared to MLRs without MSCs. The most pronounced effects were observed with MSCs from muscle tissue (90% reduction) in the mitogen-induced MLR and with MSCs from adipose tissue (85% reduction) in the allogeneic MLRs. These results suggest that MSCs from adipose tissue, which is easily optained and abundantly available, could be used to modulate GvHD and facilitate engraftment across MHC barriers. In conclusion our data demonstrate that MSCs from multiple tissues efficiently reduce T-cell activation and suggest that MSCs from adipose tissue can serve as an alternative source for MSCs to modulate GvHD or facilitate engraftment across MHC barriers. In vivo studies to test the effects on GvHD are currently under way.