Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection

Matthew J. Everly, Jason J. Everly, Brian Susskind, Paul Brailey, Lois J. Arend, Rita R. Alloway, Prabir Roy-Chaudhury, Amit Govil, Gautham Mogilishetty, Adele H. Rike, Michael Cardi, George Wadih, Amit Tevar, E. Steve Woodle

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND.: Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. METHODS.: Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. RESULTS.: Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient. CONCLUSIONS.: Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

Original languageEnglish (US)
Pages (from-to)1754-1761
Number of pages8
JournalTransplantation
Volume86
Issue number12
DOIs
StatePublished - Dec 27 2008

Keywords

  • Alloantibodies
  • B cell
  • Bortezomib
  • Plasma cell
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Transplantation

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