title: 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.
authors.affiliation: Division of Transplantation Surgery, von Liebig Transplant Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Tayyab S
authors.initials: TS
authors.lastname: Diwan
authors.forename: Suresh
authors.initials: S
authors.lastname: Raghavaiah
authors.forename: Justin M
authors.initials: JM
authors.lastname: Burns
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kremers
authors.forename: James M
authors.initials: JM
authors.lastname: Gloor
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stegall
mesh_terms: D000328:Adult; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology; D006801:Humans; D015994:Incidence; D007518:Isoantibodies / Q000097:blood*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000187:drug effects* / Q000378:metabolism*; D010951:Plasma Exchange; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D014019:Tissue Donors; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D007518:Isoantibodies; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib