Prolongation of rat‐to‐mouse islets xenograft survival by co‐transplantation of autologous IL‐10 differentiated murine tolerogenic dendritic cells

Abstract

Background Tolerogenic dendritic cells (DCs) represent a promising approach to promote transplantation tolerance. In this study, the potential of autologous bone marrow (BM)–derived murine DC to protect rat‐to‐mouse islets xenografts was analyzed. Methods Tolerogenic DCs were generated by differentiating BM cells in the presence of granulocyte‐macrophage colony‐stimulating factor and interleukin 10 (IL‐10, IL‐10 DC). The phenotype of IL‐10 DC was characterized in vitro by expression of costimulatory/inhibitory molecules (flow cytometry) and cytokines (Luminex and ELISA), their function by phagocytosis and T‐cell stimulation assays. To study transplant tolerance in vivo, rat islets were transplanted alone or in combination with autologous murine IL‐10 DC under the kidney capsule of streptozotocin‐induced diabetic C57BL/6 mice. Xenograft survival was evaluated by monitoring glycemia, cellular infiltration of xenografts by microscopy and flow cytometry 10 days post‐transplantation. Results Compared with control DC, IL‐10 DC exhibited lower levels of major histocompatibility complex class II, costimulatory molecules (CD40, CD86, CD205), lower production of pro‐inflammatory cytokines (IL‐12p70, TNF, IL‐6), and higher production of IL‐10. Phagocytosis of xenogeneic rat splenocytes was not impaired in IL‐10 DC, whereas stimulation of T‐cell proliferation was reduced in the presence of IL‐10 DC. Xenograft survival of rat islets in diabetic mice co‐transplanted with autologous murine IL‐10 DC was significantly prolonged from 12 to 21 days, without additional immunosuppressive treatment. Overall, infiltration of xenografts by T cells and myeloid cells was not different in IL‐10 DC recipient mice, but enriched for CD8+ T cells and myeloid cells with suppressor‐associated phenotype. Conclusions Autologous IL‐10‐differentiated DC with tolerogenic properties prolong rat‐to‐mouse islets xenograft survival, potentially by locally inducing immune regulatory cells, indicating their potential for regulatory immune cell therapy in xenotransplantation.

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…Prolonged xenograft survival of rat islets in diabetic mice was observed after an autologous IL-10-pulsed DC administration without any immunosuppressive treatment. The injection of IL-10-pulsed DC enriches graft infiltrating regulatory CD8 + T cells and tolerogenic myeloid cells with suppression-associated phenotypes ( 80 ). DC cotransfected Fas-L and IL-10 have more capacity to inhibit T cell activation and prolong the survival period of allografts than Fas-L alone ( 94 ).…”

Xenotransplantation: A New Era

“…Madelon et al. proved that co-transplantation of autologous IL-10 treated murine tolerogenic DCs enhanced the rat islet xenograft survival in diabetic mice ( 53 ). One group in 2018 demonstrated that NHP derived tolerogenic DCs could induce the porcine-specific Tregs ( 54 ).…”

Dendritic Cells: Versatile Players in Renal Transplantation

“…Ezzelarab et al infused donor-derived tolerogenic DCs processed by vitamin D3, IL-10 into rhesus macaque models, showing that graft survival prolonged with no evidence of host sensitization (124). Autologous tolerogenic DC infusion could also lengthen the survival time of grafts, and murine IL-10-induced DCs can function as rejection inhibitors in vivo and in vitro expressing lower levels of MHCII, CD40, CD86, CD205 (125)(126)(127).…”