The effects of an IL-21 receptor antagonist on the alloimmune response in a humanized skin transplant mouse model

K. de Leur, F. Luk, T.P.P. van den Bosch, M. Dieterich, L.J.W. van der Laan, R.W. Hendriks, M.C. Clahsen-van Groningen, F. Issa, C.C. Baan, M.J. Hoogduijn

Thursday 14 march 2019

13:27 - 13:29h at Tropentheater

Categories: Klinisch/Basaal, Parallelsessie

Parallel session: Parallelsessie XV – Basaal / Klinisch 2

Background: After solid organ transplantation, the presence of a mixed pattern rejection with features of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) is increasingly recognized. Treatment of these mixed type rejections is challenging since the majority of current immunosuppressive agents are directed towards either T-cell or B-cell mediated processes. The pleiotropic cytokine interleukin 21 (IL-21) is involved in regulating the expansion and effector function of a broad range of leucocytes, including CD4+ T cells, CD8+ T cells and B cells. In transplantation, the role of IL-21R signaling is acknowledged in several studies. However, the exact role of this cytokine in the process of allograft rejection is currently unknown. Here, we hypothesize that blockade of the IL-21 receptor (IL-21R) in a humanized skin transplant mouse model with T and B cell reconstitution prevents rejection of the human skin.

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 PBS vehicle (n=7) while the other group was treated with a humanized anti-IL-21R antibody (αIL-21R; n=8). Mice were sacrificed 30 days after cellular infusion in order to assess for evidence of skin rejection and inflammation at a single time point.

Results: In control 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 a humanized anti-IL-21R antibody (αIL-21R), these signs of allograft reactivity were significantly reduced. Of note, treatment with αIL-21R blocked phosphorylation of STAT3 and attenuated the process of T and B cell reconstitution after adoptive cellular transfer, which may contribute to the observed reduction in graft inflammation.

Conclusions: These findings demonstrate a promising role for blockade of IL-21 signaling to improve transplant outcomes.