Almost half of all organ recipients experience antibody-mediated organ rejection within ten years of the transplantation. Pharmacological agents for the suppression of chronic rejection are currently unavailable. While non-selective proteasome inhibitors can suppress antibody-mediated allograft rejection, their side effects severely limit their application.
Immunoproteasome inhibition, in contrast, has proved effective in preclinical models of autoimmune diseases and was applied over weeks without obvious adverse side effects. Using a rat model, the researchers, led by Marcus Groettrup, were able to show that immunoproteasome inhibition kills the activated plasma cells that produce allo-antibodies against the transplanted kidneys and lead to organ rejection. Selective immunoproteasome inhibition using the inhibitor ONX 0914 reduced the number of B cells and plasma cells and suppressed donor-specific allo-antibody production. The transplantations were performed by Dr Jun Li, a urological surgeon from the Cancer Institute Chongqing in China, who is an international expert for microsurgery and currently works at the University of Konstanz thanks to a scholarship awarded by the Chinese Scholarship Council.
"These results are a huge success. We can completely prevent organ rejection in all animals, also observing that allo-antibodies are virtually absent. The inflammation parameters in the transplanted kidneys decreased significantly and renal function in all recipients is excellent", summarises Marcus Groettrup, adding that these results suggest immunoproteasome inhibition as a promising therapeutic approach to suppress chronic antibody-mediated rejection.