Inducible Costimulator Gene Transduced Bone Marrow Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in a Mouse Haploidentical Model.

Abstract 2996

It is reported that both block of costimulator (ICOS) or its ligand signal pathway and transfusion of mesenchymal stem cells (MSCs) can reduce the severity of acute graft-versus-host disease (GvHD). Using a MHC-haploidentical murine model of acute GvHD, we investigated the effects of MSC^-ICOS-EGFP, bone marrow derived MSCs transduced with ICOS-gene using an adenoviral vector, on acute GvHD. Lethally irradiated CB6F1 mice were transplanted with bone marrow cells and spleen cells from C57BL/6 mice, and injected with MSC^-ICOS-EGFP, MSCs, ICOS-Ig fusion protein or the diluent (control), respectively. Survival in recipients of MSC^-ICOS-EGFP was significantly higher than that in GVHD group (74.29±7.39% vs 0, P=0.000, n=35), and also higher than in MSCs, ICOS-Ig, or MSCs+ICOS-Ig groups (74.29±7.39% vs 42.86±8.36% or 48.57±8.45% or 50.43±8.45%, P=0.0039 or 0.0323 or 0.0418, n=35). The lower mortality in recipients of MSC^-ICOS-EGFP was related to lower incidence of acute GvHD. MSC^-ICOS-EGFP can reduce the number of CD4⁺T cells in the early stage of GvHD due to the increased apoptosis, and it can produce CD4⁺CD25⁺Treg cells meanwhile. The effect on GvHD in recipient of MSC^-ICOS-EGFP was also associated with higher serum levels of IL-4, IL-10 and lower levels of IFN-γ, IL-2, IL-12, IL-17A, as well as inducing expression of GATA-3, STAT6 transcription factors while inhibiting expression of T-bet, STAT4, ROR-rt in spleen. In vitro, the CD4⁺T cells of donor were sharply inhibited by MSC^-ICOS-EGFP and the B7h blockade. In MLRs we can also detect lower levels of IFN-γ, IL-2and higher levels of IL-4, IL-10. These data indicate that MSC^-ICOS-EGFP is a more prospective strategy for acute GvHD prevention, which had a synergism effect between MSCs and ICOS-Ig. The mechanisms of MSC^-ICOS-EGFP on acute GvHD were closely associated with modulation of CD4⁺T cells, CD4⁺CD25⁺Tregs, and regulation of the Th1/Th2/Th17 balance in the early stage of GvHD.