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

Abstract

In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs 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 MSCs ICOS-EGFP , MSCs, MSCs 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 the C57BL/6 ® CB6F1 HSCT model, the long-term survival in the MSC ICOS-EGFP group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p < 0.01), and this survival rate was also higher than that in the MSC, ICOS-Ig, or MSC + 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 MSCs 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 until day 14 (p < 0.05 on days 2, 3, 7, and 14). Furthermore, we demonstrated that MSCs ICOS-EGFP were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-g, IL-2, IL-12, and IL-17A were detected in the MSC ICOS-EGFP group. The MSCs ICOS-EGFP could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-gt expression. Our results showed that injection of MSCs ICOS-EGFP is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage.

Immunomodulatory effects of OX40Ig gene-modified adipose tissue-derived mesenchymal stem cells on rat kidney transplantation

“…Thus, as gene delivery vehicles, the localization of ADSCs combined with costimulation blockade may provide a new opportunity for successful therapy (15,42). In this study, our results revealed that the administration of OX40Ig gene-modified ADSCs resulted in a modest, but greater prolongation in the survival time of renal grafts compared with ADSC monotherapy.…”

pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis

“…Animals were monitored daily for any clinical features including alopecia, submandibular erythema, hunchback appearance, and piloerection. A clinical disease severity score was assessed, where each of the aforementioned features were given a score of 1, as described previously (44,45).…”

Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models

“…There was significant heterogeneity among the studies (I 2 = 66.1%, P = 2.12×10 −18 ) (Figure 1 ). In addition, 29 studies involving 41 comparisons examined the effect of MSCs on aGVHD-associated clinical scores [ 14 , 15 , 17 , 19 , 20 , 22 , 24 , 27 , 28 , 33 , 34 , 36 – 39 , 42 , 44 , 46 , 47 , 49 – 52 , 55 , 57 – 59 , 61 , 62 ]. The pooled analysis indicated that aGVHD-associated clinical scores were significantly lower in the MSC groups than in the control groups (SMD = −3.60, 95% CI −4.43 to −2.76, P = 3.61×10 −17 ) (Figure 2 ).…”