Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation

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2018
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Chronic antibody-mediated rejection is the major cause of fading allograft function and loss after renal transplantation. Currently, pharmacological agents for the suppression of chronic antibody-mediated rejection are lacking. Non-selective proteasome inhibitors suppress antibody-mediated allograft rejection. However, extensive adverse side effects of these inhibitors severely limit their application. In contrast, immunoproteasome inhibition is effective in preclinical models of autoimmune diseases and was applied over weeks without obvious adverse side effects. ONX 0914, an immunoproteasome subunit LMP7 (β5i)-selective inhibitor, impeded the chronic rejection of kidneys transplanted from Fischer to allogeneic Lewis rats. ONX 0914 inhibited immunoproteasome induction both in immune organs and renal allografts. Selective immunoproteasome inhibition reduced the numbers of B and plasma cells, and suppressed donor-specific alloantibody production. The infiltration of T cells, B cells and macrophages as well as interferon-γ, interleukin-17, IgG and complement deposition were reduced in renal allografts of ONX 0914-treated recipients. Chronic nephropathy was ameliorated and renal allograft function preserved, enabling long-term survival of recipients. Thus, our studies define a critical role of the immunoproteasome in chronic kidney allograft rejection and suggest immunoproteasome inhibition as a promising therapeutic approach to suppress chronic antibody-mediated rejection.

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570 Biowissenschaften, Biologie
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chronic rejection; immunoproteasome; kidney transplantation
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ISO 690LI, Jun, Michael BASLER, Gerardo Omar ALVAREZ SALINAS, Thomas BRUNNER, Christopher J. KIRK, Marcus GRÖTTRUP, 2018. Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation. In: Kidney International. 2018, 93(3), pp. 670-680. ISSN 0085-2538. eISSN 1523-1755. Available under: doi: 10.1016/j.kint.2017.09.023
BibTex
@article{Li2018-03Immun-40987,
  year={2018},
  doi={10.1016/j.kint.2017.09.023},
  title={Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation},
  number={3},
  volume={93},
  issn={0085-2538},
  journal={Kidney International},
  pages={670--680},
  author={Li, Jun and Basler, Michael and Alvarez Salinas, Gerardo Omar and Brunner, Thomas and Kirk, Christopher J. and Gröttrup, Marcus}
}
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