Immunomodulation of cell-penetrating tat-metallothionein for successful outcome of xenotransplanted pancreatic islet

Abstract

Pancreatic islet transplantation is a promising treatment for treatment of type 1 diabetes; however, transplantation outcomes have been disappointing due to early graft loss that is mediated by many immune responses. Immune cells not only directly damaged islet but also produced reactive oxygen species (ROS), which is highly toxic to islet cells. Metallothionein (MT) can provide protection against oxidative stress by scavenging various ranges of ROS including superoxide, hydroxyl radical, hydrogen peroxide and nitric oxide. For scavenging immune response-induced ROS, cell-penetrating Tat peptide-metallothionein (Tat-MT) was delivered into islets. The viability of Tat-MT-treated islets was not damaged during co-culture with macrophages or ROS-generating paraquat. When Tat-MT-treated islets were xenotransplanted, ROS production was significantly attenuated at the islets. Eventually, the survival time of Tat-MT-treated islets was significantly enhanced without any immunosuppressant medicine. Additionally, we confirmed that the survival time of Tat-MT-treated islets in all animals was dramatically improved when accompanied with low dose immunosuppressive agents (tacrolimus and anti-CD154 monoclonal antibody), indicating that Tat-MT delivery could have synergistic effect with immunosuppressants. Collectively, this new combination therapy of Tat-MT delivery with low dose immunosuppressant would be a powerful remedy for successful outcome of islet xenotransplantation.