Premium
Prolongation of rat‐to‐mouse islets xenograft survival by co‐transplantation of autologous IL‐10 differentiated murine tolerogenic dendritic cells
Author(s) -
Madelon Natacha,
Montanari Elisa,
Gruaz Lyssia,
Pimenta Joel,
Muller Yannick D.,
Bühler Leo H.,
Puga Yung Gisella L.,
Seebach Jörg D.
Publication year - 2020
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12584
Subject(s) - dendritic cell , transplantation , mixed lymphocyte reaction , immunology , islet , interleukin 10 , flow cytometry , immune tolerance , t cell , medicine , cytokine , biology , immune system , endocrinology , insulin
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.