Inducible costimulator gene transduced bone marrow derived mesenchymal stem cells attenuate the severity of acute graft-versus-host disease in mouse models.
In allogeneic transplantation murine models, ICOS gene transduced bone marrow derived mesenchymal stem cells (MSC(-ICOS-EGFP)) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSC(-ICOS-EGFP), MSCs, MSC(-EGFP), ICOS-Ig fusion protein, MSCs+ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4(+) T cell apoptosis and proliferation, and Th1/Th2/Th17 effecter cell polarization were evaluated. In C57BL/6?CB6F1 HSCT model, the long-term survival in MSC(-ICOS-EGFP) group was higher than that in GvHD group (74.29±7.39% vs 0, P=0.00), and this survival rate was also higher than that in the MSCs, ICOS-Ig, or MSCs+ICOS-Ig groups (42.86±8.36% P=0.004, 48.57±8.45% P=0.03, or 50.43±8.45% P=0.04, respectively). The survival advantages of MSC(-ICOS-EGFP) treated group were confirmed in the C57BL/6?BALB/c HSCT model. In both HSCT models, the low mortality in the MSC(-ICOS-EGFP) group was associated with lower incidence and severity of acute GvHD. Treatment with MSC(-ICOS-EGFP) induced more CD4(+) T cell apoptosis compared with that in the GvHD group. The effect on CD4(+) T cells was shown as early as day 2 and maintained till day 14 (P<0.05 on day 2, 3, 7, and 14). Furthermore, we demonstrated that MSC(-ICOS-EGFP) was able to suppress Th1 and Th17 polarization and promote Th2 polarization in both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-?, IL-2, IL-12, IL-17A were detected in the MSC(-ICOS-EGFP) group. MSC(-ICOS-EGFP) could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-rt expression. Our results showed that MSC(-ICOS-EGFP) is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSCs immune modulation and ICOS-B7h pathway blockage.