Kitty de Leur1,2, Franka Luk1, Thierry P P van den Bosch3, Marjolein Dieterich1, Luc J W van der Laan2, Rudi W Hendriks4, Marian C Clahsen-van Groningen3, Fadi Issa5, Carla C Baan1, Martin J Hoogduijn1. 1. The Rotterdam Transplant Group, Erasmus MC, Department of Internal Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands. 2. Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 3. Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 4. Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 5. Nuffield Department of Surgical Sciences, Transplantation Research Immunology Group, University of Oxford, Oxford, United Kingdom.
Abstract
BACKGROUND: Interleukin 21 (IL-21) is involved in regulating the expansion and effector function of a broad range of leukocytes, including T cells and B cells. In transplantation, the exact role of IL-21 in the process of allograft rejection is unknown. To further explore this, the aim of this study is to test the effect of an IL-21 receptor (IL-21R) blocking antibody on the early phase of allograft rejection in a humanized skin transplantation model in mice reconstituted with human T and B cells. METHODS: Immunodeficient Balb/c IL2rγRag2 mice were transplanted with human skin followed by adoptive transfer of human allogeneic splenocytes. Control animals were treated with a phosphate buffered saline vehicle while the other group was treated with a humanized anti-IL-21R antibody (αIL-21R). RESULTS: In the phosphate buffered saline-treated animals, human skin allografts were infiltrated with lymphocytes and developed a thickened epidermis with increased expression of the inflammatory markers Keratin 17 (Ker17) and Ki67. In mice treated with αIL-21R, these signs of allograft reactivity were significantly reduced. Concordantly, STAT3 phosphorylation was inhibited in this group. Of note, treatment with αIL-21R attenuated the process of T and B cell reconstitution after adoptive cellular transfer. CONCLUSIONS: These findings demonstrate that blockade of IL-21 signaling can delay allograft rejection in a humanized skin transplantation model.
BACKGROUND: Interleukin 21 (IL-21) is involved in regulating the expansion and effector function of a broad range of leukocytes, including T cells and B cells. In transplantation, the exact role of IL-21 in the process of allograft rejection is unknown. To further explore this, the aim of this study is to test the effect of an IL-21 receptor (IL-21R) blocking antibody on the early phase of allograft rejection in a humanized skin transplantation model in mice reconstituted with human T and B cells. METHODS: Immunodeficient Balb/c IL2rγRag2 mice were transplanted with human skin followed by adoptive transfer of human allogeneic splenocytes. Control animals were treated with a phosphate buffered saline vehicle while the other group was treated with a humanized anti-IL-21R antibody (αIL-21R). RESULTS: In the phosphate buffered saline-treated animals, human skin allografts were infiltrated with lymphocytes and developed a thickened epidermis with increased expression of the inflammatory markers Keratin 17 (Ker17) and Ki67. In mice treated with αIL-21R, these signs of allograft reactivity were significantly reduced. Concordantly, STAT3 phosphorylation was inhibited in this group. Of note, treatment with αIL-21R attenuated the process of T and B cell reconstitution after adoptive cellular transfer. CONCLUSIONS: These findings demonstrate that blockade of IL-21 signaling can delay allograft rejection in a humanized skin transplantation model.
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