Inhibition of cardiac allograft rejection in mice using interleukin‐35‐modified mesenchymal stem cells

: Interleukin-35 (IL-35) is a cytokine recently discovered to play a potent immunosuppressive role by intensifying the functions of regulatory T cells and inhibiting the proliferation and functions of T helper 1 and T helper 17 cells. Mesenchymal stem cells (MSCs) have recently emerged as promising candidates for cell-based immune therapy, and our previous study showed that IL-35 gene modification can effectively enhance the therapeutic effect of MSCs in vitro. In this study, we isolated adipose tissue-derived MSCs in vitro and infected them with lentiviral vectors overexpressing the IL-35 gene, thereby creating IL-35-MSCs. Subsequently, IL-35-MSCs were then injected into mice of the allogeneic heterotopic abdominal heart transplant model to determine their effect on allograft rejection. The results showed that IL-35-MSCs could continuously secrete IL-35 in vivo and in vitro, successfully alleviate allograft rejection and prolong graft survival. In addition, compared to MSCs, IL-35-MSCs showed a stronger immunosuppressive ability and further reduced the percentage of Th17 cells, increased the proportion of CD4+ Foxp3+ T cells, and regulated Th1/Th2 balance in heart transplant mice. These findings suggest that IL-35-MSCs have more advantages than MSCs in inhibiting graft rejection and may thus provide a new approach for inducing immune tolerance during transplantation.