title: Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients.
abstract: BACKGROUND
  High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA.
  
  
  METHODS
  Patients received four intravenous dose of bortezomib (1.3 mg/m(2)) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective.
  
  
  RESULTS
  AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment.
  
  
  CONCLUSIONS
  Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.
authors.affiliation: Department of Pediatrics, Cardiology Section, University of Arkansas for Medical Sciences, Cardiology, Arkansas Children's Hospital, 1 Children's Way, Little Rock, AR, USA.
authors.forename: William Robert
authors.initials: WR
authors.lastname: Morrow
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Frazier
authors.forename: William T
authors.initials: WT
authors.lastname: Mahle
authors.forename: Terry O
authors.initials: TO
authors.lastname: Harville
authors.forename: Sherry E
authors.initials: SE
authors.lastname: Pye
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Knecht
authors.forename: Emily L
authors.initials: EL
authors.lastname: Howard
authors.forename: R Neal
authors.initials: RN
authors.lastname: Smith
authors.forename: Robert L
authors.initials: RL
authors.lastname: Saylors
authors.forename: Xiomara
authors.initials: X
authors.lastname: Garcia
authors.forename: Robert D B
authors.initials: RD
authors.lastname: Jaquiss
authors.forename: E Steve
authors.initials: ES
authors.lastname: Woodle
mesh_terms: D000293:Adolescent; D000328:Adult; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002648:Child; D006084:Graft Rejection / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000097:blood* / Q000276:immunology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D012189:Retrospective Studies; D014019:Tissue Donors
chemical_list: D001897:Boronic Acids; D006680:HLA Antigens; D007518:Isoantibodies; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib