title: Differential effect of bortezomib on HLA class I and class II antibody.
abstract: BACKGROUND
  Bortezomib has been used to reduce HLA antibody in patients either before transplantation or as treatment for antibody-mediated rejection (AMR). Reports on its efficacy show mixed results. The mechanism of action of this agent is via proteasome inhibition. The primary route of synthesis of HLA class I molecules is dependent on peptide generation by the proteasome, whereas that of class II is not. We observed a differential effect of bortezomib on class I versus class II antibody and hypothesized that this was related to a reduced expression of class I HLA antigens.
  
  
  METHODS
  The effect of bortezomib on HLA antibody levels was evaluated in 13 patients who were desensitized for incompatible renal transplantation. We calculated the percent difference in HLA antibody level before and after bortezomib treatment and the impact of bortezomib on HLA expression in lymphocytes of healthy control subjects.
  
  
  RESULTS
  On average, the level of HLA class I donor-specific antibody (DSA) decreased by 32%, whereas that of class II DSA increased by 29%. In vitro bortezomib treatment of lymphocytes resulted in a mean decrease of 23% in MHC class I expression on B lymphocytes and no change (+1.08%) in MHC class II expression (P=0.0003). The amount of intracellular class I molecules was reduced by a mean of 29% with bortezomib.
  
  
  CONCLUSIONS
  These data indicate that bortezomib reduces HLA class I antibody more effectively than class II antibody. This difference may be due to the reduced expression of class I molecules resulting from treatment with this proteasome inhibitor.
authors.affiliation: 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. 3 Address correspondence to: Mary Carmelle Philogene, Ph.D., Immunogenetics Laboratory, 2041 E. Monument Street, Baltimore, MD 21205.
authors.forename: Mary Carmelle
authors.initials: MC
authors.lastname: Philogene
authors.forename: Paul
authors.initials: P
authors.lastname: Sikorski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Montgomery
authors.forename: Mary S
authors.initials: MS
authors.lastname: Leffell
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Zachary
mesh_terms: D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006084:Graft Rejection; D015395:Histocompatibility Antigens Class I / Q000187:drug effects* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000276:immunology* / Q000601:surgery; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D012189:Retrospective Studies
chemical_list: D000906:Antibodies; D001897:Boronic Acids; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib