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The Effects of an IL-21 Receptor Antagonist on the Alloimmune Response in a Humanized Mouse Skin Transplant Model

de Leur, Kitty MSc1,2; Luk, Franka PhD1; van den Bosch, Thierry P.P. PhD3; Dieterich, Marjolein BSc1; van der Laan, Luc J.W. PhD2; Hendriks, Rudi W. PhD4; Clahsen-van Groningen, Marian C. MD, PhD3; Issa, Fadi MD, PhD5; Baan, Carla C. PhD1; Hoogduijn, Martin J. PhD1

doi: 10.1097/TP.0000000000002773
Original Basic Science–General
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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 IL2rγ−/−Rag2−/− 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.

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.

Received 12 December 2018. Revision received 14 April 2019.

Accepted 16 April 2019.

This work was supported by a grant from the Erasmus MC, University Medical Center, Rotterdam, awarded by the Erasmus MC Medical research advisory committee (Mrace), grant no. 343564.

The authors declare no conflicts of interest.

K.dL. participated in research design, performing the research, data analysis, and writing of the article. F.L. participated in research design, performing the research, data analysis, and revision of the article. T.P.P.v.d.B. provided technical help and revision of the article. M.D. provided technical help and revision of the article. L.J.W.v.d.L. participated in research design and revision of the article. R.W.H. participated in research design and revision of the article. M.C.C.-V.G. provided analytical tools and revision of the article. F.I. provided technical help and revision of the article. C.C.B. participated in research design and revision of the article. M.J.H. participated in research design, performing the research, and writing of the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Martin J. Hoogduijn, PhD, Erasmus MC, Room Na-516, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands. (m.hoogduijn@erasmusmc.nl).

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