Introduction: Among various attempts to improve islet transplantation outcomes, elucidating the mechanism of enhanced immune cell responses of innate and acquired immune systems to grafts triggered by IBMIR is one of the most important issues. We have previously reported that simultaneous transplantation of cytokine-stimulated Mesenchymal Stem Cells (MSC) suppresses the immune response in the liver and improves transplantation outcomes in a mouse intraportal islet transplantation model.
In the present study, we compared Stem Cells from Human Exfoliated Deciduous teeth (SHED) and bone marrow-derived MSC to examine whether a similar phenomenon is observed in the human immune system.
Methods and Results: SHED was stimulated with TNF-α, IL-1β and IFN-γ, which were increased by IBMIR in the liver. The cell surface antigen of stimulated SHED was assessed by FACS analysis. SHED showed no enhancement of MHC class 2 expression upon cytokine stimulation, confirming a more stable cell population than MSC (n=6). Furthermore, PDL1, which is not expressed in naive condition, was significantly expressed by cytokine stimulation in both MSC and SHED. Next, the production ability of inhibitory factors was confirmed by ELISA: IDO and TGF-β were significantly produced only in SHED under cytokine stimulation, and the production ability of PGE2 was significantly enhanced in SHED (n=6). Furthermore, a significant inhibitory effect on the activation of CD3/CD28 magnetic bead-stimulated human PBMC in SHED was confirmed (P<0.01, n=6). We also confirmed that this effect was significantly cancelled by blocking the PD1-PDL1 pathway, and that the inhibitory effect was diminished by inhibiting cell contact, using a separate well system. Furthermore, the cytotoxic activity of activated PBMC on iPS-derived human β-cells was confirmed and was clearly inhibited in the presence of cytokine-stimulated SHED (P<0.01, n=6).
Conclusion: The immunosuppressive effect of SHED was confirmed to be due to mechanisms mediated by both humoral factors and cellular contact. Simultaneous transplantation with islets is expected to allow efficient islet transplantation.