Prolongation of rat‐to‐mouse islets xenograft survival by co‐transplantation of autologous IL‐10 differentiated murine tolerogenic dendritic cells. (26th January 2020)

• Record Type: Journal Article
• Authors: Madelon, Natacha; Montanari, Elisa; Gruaz, Lyssia; Pimenta, Joel; Muller, Yannick D.; Bühler, Leo H.; Puga Yung, Gisella L.; Seebach, Jörg D.
• Is Part Of: Xenotransplantation. Volume 27:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-01-26
• Subjects: IL‐10 -- rat‐to‐mouse islets xenograft -- tolerogenic DC; Xenografts -- Periodicals; Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/xen.12584
• Languages: English
• ISSNs: 0908-665X

Abstract

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.