The impact of proteasome inhibition on alloantibody-producing plasma cells in vivo

Transplantation. 2011 Mar 15;91(5):536-41. doi: 10.1097/TP.0b013e3182081333.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Dose-Response Relationship, Drug
  • Female
  • Graft Rejection / epidemiology
  • Graft Rejection / immunology
  • Humans
  • Incidence
  • Isoantibodies / blood*
  • Kidney Transplantation / immunology*
  • Male
  • Middle Aged
  • Plasma Cells / drug effects*
  • Plasma Cells / metabolism*
  • Plasma Exchange
  • Prospective Studies
  • Protease Inhibitors / pharmacology*
  • Proteasome Inhibitors*
  • Pyrazines / pharmacology*
  • Tissue Donors
  • Treatment Outcome

Substances

  • Boronic Acids
  • Isoantibodies
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib