Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients: A pilot study

Hidetaka Hara, Andrew Bentall, Cassandra Long, Jason Fang, Oleg Andreyev, John Lunz, Mohamed Ezzelarab, Kareem M. Abu-Elmagd, Ron Shapiro, David Ayares, Mark Stegall, David K.C. Cooper

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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.

Original languageEnglish (US)
Pages (from-to)429-437
Number of pages9
JournalXenotransplantation
Volume20
Issue number6
DOIs
StatePublished - Nov 2013

Keywords

  • antibodies, anti-Gal
  • antibodies, anti-nonGal
  • antibodies, anti-pig
  • bortezomib

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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    Hara, H., Bentall, A., Long, C., Fang, J., Andreyev, O., Lunz, J., Ezzelarab, M., Abu-Elmagd, K. M., Shapiro, R., Ayares, D., Stegall, M., & Cooper, D. K. C. (2013). Minimal effect of bortezomib in reducing anti-pig antibodies in human leukocyte antigen-sensitized patients: A pilot study. Xenotransplantation, 20(6), 429-437. https://doi.org/10.1111/xen.12052