Proteasome inhibition for antibody-mediated rejection

Curr Opin Organ Transplant. 2009 Dec;14(6):662-6. doi: 10.1097/MOT.0b013e328330f304.

Abstract

Purpose of review: The purpose of this review is to describe the biochemistry and physiology of proteasome inhibition and to discuss recent studies with proteasome inhibitor therapy in organ transplantation.

Recent findings: Traditional antihumoral therapies do not deplete plasma cells, the source of antibody production. Proteasome inhibition depletes both transformed and nontransformed plasma cells in animal models and human transplant recipients. Bortezomib is a first in a class proteasome inhibitor that has been shown to effectively treat antibody-mediated rejection in kidney transplant recipients. In this experience, bortezomib provided reversal of histologic changes and also induced a reduction in donor-specific anti-HLA antibody levels. Recent experiences have also shown that bortezomib reduces donor-specific anti-human leukocyte antigen antibody in the absence of rejection. Finally, evidence has been presented that bortezomib therapy depletes human leukocyte antigen-specific antibody producing plasma cells.

Summary: Proteasome inhibition induces a complex series of biochemical events that results in pleiotropic effects on multiple cell populations, and plasma cells in particular. Initial clinical results have provided evidence that bortezomib effectively treats antibody-mediated rejection and acute cellular rejection and reduces or eliminates donor-specific anti-human leukocyte antigen antibody. Carefully designed clinical trials are needed to accurately define the role of proteasome inhibition in transplant recipients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies / blood
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Disease Models, Animal
  • Graft Rejection / enzymology
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects*
  • HLA Antigens / immunology
  • Humans
  • Immunity, Humoral / drug effects*
  • Kidney Transplantation / adverse effects*
  • Plasma Cells / drug effects
  • Plasma Cells / enzymology
  • Plasma Cells / immunology
  • Protease Inhibitors / therapeutic use*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Pyrazines / therapeutic use*

Substances

  • Antibodies
  • Boronic Acids
  • HLA Antigens
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib
  • Proteasome Endopeptidase Complex