The Impact of Proteasome Inhibition on Alloantibody-Producing Plasma Cells In Vivo

Abstract

BACKGROUND: Donor specific alloantibody producing plasma cells (DSA-PCs) appear resistant to conventional immunosuppressive agents. This study aimed to determine the impact of pretransplant monotherapy with the proteasome inhibitor bortezomib on DSA-PCs in sensitized renal allograft candidates and to assess if DSA-PC depletion would enhance the efficacy of DSA removal using plasma exchange (PE). METHODS: Only patients with DSA levels considered too high to successfully undergo transplantation with PE alone were included in this study: i.e. those with a baseline B flow cytometric crossmatch (BFXM) >450 against a potential living donor.Four sensitized patients received 4 doses (1.3 mg/m/dose) of bortezomib and 4 received 16 doses. The number of DSA-PCs was determined pre and post-treatment using an ELISPOT assay. Five of these patients underwent post-treatment PE and their response was compared to 8 highly-sensitized patients (BFXM >450) who underwent PE alone. RESULTS: When considering all 8 patients as one group, bortezomib treatment decreased DSA-PCs in the marrow (mean±SD=16.7±14.5 DSA-PCs/ml pre-treatment vs. 6.2±3.6 DSA-PCs/ml after treatment, P=0.048). In the time frame of the study, bortezomib alone did not decrease serum DSA levels. However, five bortezomib treated patients underwent PE and showed a greater decease in DSA compared to the historical control group of 8 sensitized patients who underwent PE alone (mean decrease in BFXM channel shift=272.6±92.1 with bortezomib vs 95.4±72.2 in PE alone P=0.008). CONCLUSIONS: Bortezomib depletes DSA-PCs and appears to potentiate DSA removal by PE in sensitized renal transplant recipients.