title: Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients: a pilot study.
abstract: BACKGROUND
  Bortezomib, a proteasome inhibitor used to treat multiple myeloma, has been administered (± plasma exchange ± intravenous immunoglobulin [IVIg]) in attempts to reduce antibodies against human leukocyte antigens (HLA) in sensitized patients undergoing organ transplantation. To our knowledge, bortezomib has not been investigated for its effect on natural anti-pig antibodies. If bortezomib could reduce the production of anti-pig antibodies, this would likely be beneficial to the outcome of pig organ grafts in primates.
  
  
  METHODS
  Nine patients received bortezomib either to reduce anti-HLA antibody levels before organ allotransplantation or to treat antibody-mediated rejection. Patients at the Mayo Clinic (Group 1; n = 4) received bortezomib alone, whereas at the UPMC (Group 2; n = 5), this was combined with plasmaphereses ± IVIg in some cases. Anti-pig IgM and IgG levels against wild-type (WT) and α1,3-galactosyltransferase gene knockout (GTKO) pig aortic endothelial cells (flow cytometry-relative mean fluorescence intensity) and anti-Gal IgM and IgG (ELISA-OD480 nm ) were measured pre- and post-bortezomib therapy.
  
  
  RESULTS
  Mean anti-pig IgM levels were 11.2 (WT) and 1.9 (GTKO) pre-bortezomib treatment and 9.4 (WT: P = 0.02) and 1.7 (GTKO: P = 0.33) post-bortezomib treatment, respectively. Mean anti-pig IgG levels were 4.3 (WT) and 1.5 (GTKO) pre-bortezomib treatment and 3.6 (WT: P = 0.21) and 1.4 (GTKO: P = 0.20) post-bortezomib treatment, respectively. Mean anti-Gal IgM and IgG levels were 0.7 and 1.1, respectively, pre-treatment, and 0.6 (P = 0.03) and 1.1 (NS), respectively, post-treatment. When the data were analyzed in Groups 1 and 2 separately, there were no significant differences between the pre- and post-bortezomib levels of anti-pig, anti-non-Gal, or anti-Gal IgM or IgG.
  
  
  CONCLUSIONS
  From this limited study, we conclude that bortezomib might reduce anti-Gal IgM levels in primates, but, in this respect alone, is unlikely to have any significant effect on the outcome of GTKO pig organ transplantation.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.forename: Andrew
authors.initials: A
authors.lastname: Bentall
authors.forename: Cassandra
authors.initials: C
authors.lastname: Long
authors.forename: Jason
authors.initials: J
authors.lastname: Fang
authors.forename: Oleg
authors.initials: O
authors.lastname: Andreyev
authors.forename: John
authors.initials: J
authors.lastname: Lunz
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ezzelarab
authors.forename: Kareem M
authors.initials: KM
authors.lastname: Abu-Elmagd
authors.forename: Ron
authors.initials: R
authors.lastname: Shapiro
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.forename: Mark
authors.initials: M
authors.lastname: Stegall
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
mesh_terms: D000328:Adult; D064591:Allografts; D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000096:biosynthesis* / Q000097:blood; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D005260:Female; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D055786:Gene Knockout Techniques; D006680:HLA Antigens / Q000276:immunology*; D064593:Heterografts; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D034421:Sus scrofa / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D000910:Antibodies, Heterophile; D001897:Boronic Acids; D006680:HLA Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine
keywords: antibodies, anti-Gal; antibodies, anti-nonGal; antibodies, anti-pig; bortezomib