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

Abstract

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.

On the role of the immunoproteasome in transplant rejection

“…Plasma cells that synthesize large amounts of immunoglobulins have a relatively high sensitivity to bortezomib, which partly explains the clinical success of bortezomib in treating plasma cell-derived multiple myelomas. Li et al showed that immunoproteasome inhibition in rats prevented alloantibody production and reduced the number of plasma cells in an antibody-mediated kidney allograft (Li et al 2018). Hence, it seems likely that immunoproteasome inhibition in plasma cells induces ER stress leading to apoptotic plasma cell death and prevention of alloantibody production.…”

“…Furthermore, in an in vitro humoral alloimmunity model, ONX 0914 was shown to decrease alloantibody production (Eleftheriadis et al 2017). In a recent study, the effect of immunoproteasome inhibition has been investigated in a rat kidney transplantation model (Li et al 2018). In this transplantation model, kidneys transplanted from Fischer to allogeneic Lewis rats induce a chronic antibody-mediated allograft rejection.…”

“…The altered class I peptidome on immunoproteasome-containing cells influences pathogen-induced cytotoxic T lymphocyte (CTL) responses, pathogen clearance, and shapes the CTL repertoire (Basler et al 2004(Basler et al , 2006Chen et al 2001;Chou et al 2008;Ersching et al 2016;Guimaraes et al 2018;Hutchinson et al 2011). Due to the use of immunoproteasome-selective inhibitors in recent years, it became evident that the immunoproteasome has, apart from its role in antigen processing, an important function in T helper cell differentiation Guo et al 2018;Kalim et al 2012;Muchamuel et al 2009;Xiao et al 2017), in macrophage polarization (Chen et al 2016), in brain inflammation (Kremer et al 2010;, in inflammatory cytokine production (Basler et al 2010(Basler et al , 2014Farini et al 2016;Guo et al 2018;Muchamuel et al 2009), in autoimmune diseases (Basler et al 2010(Basler et al , 2014Ichikawa et al 2012;Liu et al 2017, b;Muchamuel et al 2009;Nagayama et al 2012;Xiao et al 2017), in colitis-associated cancers (Koerner et al 2017;Vachharajani et al 2017), in angiogenesis (Chen et al 2018), in viral myocarditis (Althof et al 2018), in the activation of lymphocytes (Santos et al 2017;Sula Karreci et al 2016), and organ transplantation (Li et al 2018;Sula Karreci et al 2016).…”

The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis

“…Proteasome inhibition is particularly efficient in secretory cells such as plasma cells which has led to the approval of several proteasome inhibitors such as Velcade™, Kyprolis™ , and Ninlaro™ for the treatment of multiple myeloma (see here for examples of clinical trials with proteasome inhibitors). This observation led to the application of proteasome and specific immunoproteasome inhibitors in allograft rejection in humans and several experimental models, however, with mixed results [106][107][108][109][110] . It might be worth considering this therapeutic concept also for B-cell driven autoimmune responses including SSc as suggested previously for autoimmune diseases with renal manifestations 111 .…”

Decreased Expression of MicroRNA-107 in B Lymphocytes of Patients with Antibody-Mediated Renal Allograft Rejection

“…The continuous development of surgical techniques and the use of new immunosuppressive agents have significantly improved the short-term survival of renal transplant patients, but the long-term survival rate remains unsatisfactory. A large number of studies showed that antibody-mediated rejection (antibody-mediated renal allograft rejection, ABMR) is one of the most important mechanisms of rejection after renal transplantation (Drachenberg and Papadimitriou 2013;Zhao et al 2017;Li et al 2018). ABMR results in 30-50% of acute rejection episodes and more than 60% of late graft dysfunction.…”