title: Reduction of alloantibodies via proteasome inhibition in cardiac transplantation.
abstract: BACKGROUND
  The presence of alloantibodies in patients awaiting heart transplantation is associated with increased waiting time to transplant, increased risk of rejection after transplant, an increased risk of cardiac allograft vasculopathy, and decreased survival. So far, treatments to reduce circulating antibodies to allow transplantation have been limited. We report the first clinical experience using a plasma-cell-depleting strategy with bortezomib to reduce anti-HLA antibodies in the heart transplant population.
  
  
  METHODS
  Six patients awaiting cardiac transplantation demonstrated persistently elevated anti-HLA antibodies, despite receiving a course of treatment with intravenous immunoglobulin (IVIg) and rituximab. These patients then underwent supplemental therapy with bortezomib in conjunction with plasmapheresis. One additional patient awaiting cardiac transplantation with elevated anti-HLA antibodies required bortezomib treatment for amyloidosis. Antibody strength was monitored after completion of treatment by solid-phase (single-antigen-bead) assay.
  
  
  RESULTS
  The mean calculated panel-reactive antibody (cPRA) was reduced from 62% to 35% following a course of bortezomib (p = 0.01). Six of 7 patients demonstrated a significant decline in antibody levels. One patient remained refractory to desensitization therapy and died from sepsis while awaiting heart transplantation. Four patients successfully underwent cardiac transplantation without evidence of rejection or graft dysfunction. One patient developed early post-transplant graft dysfunction and died at 1 month from sepsis. Infection was the most common adverse effect associated with desensitization.
  
  
  CONCLUSIONS
  In this pilot study, use of plasmapheresis and bortezomib appeared to decrease cPRA, even in patients refractory to desensitization with IVIg/rituximab, thus increasing the chances that an acceptable donor heart will be available for the sensitized patient awaiting heart transplantation. However, desensitization is associated with an increased risk of infection. Further studies are warranted to determine whether the benefits of desensitization using this strategy outweigh the risks.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California 90048, USA. jignesh.patel@cshs.org
authors.forename: Jignesh
authors.initials: J
authors.lastname: Patel
authors.forename: Matthew
authors.initials: M
authors.lastname: Everly
authors.forename: David
authors.initials: D
authors.lastname: Chang
authors.forename: Michelle
authors.initials: M
authors.lastname: Kittleson
authors.forename: Elaine
authors.initials: E
authors.lastname: Reed
authors.forename: Jon
authors.initials: J
authors.lastname: Kobashigawa
mesh_terms: D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007239:Infections / Q000453:epidemiology; D007518:Isoantibodies / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010956:Plasmapheresis; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001897:Boronic Acids; D016756:Immunoglobulins, Intravenous; D007518:Isoantibodies; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease