title: Proteasome inhibitor-based therapy for antibody-mediated rejection.
abstract: The development of donor-specific anti-human leukocyte antigen antibodies (DSAs) following renal transplantation significantly reduces long-term renal graft function and survival. The traditional therapies for antibody-mediated rejection (AMR) have provided inconsistent results and transient effects that may be due to a failure to deplete mature antibody-producing plasma cells. Proteasome inhibition (PI) is a novel AMR therapy that deletes plasma cells. Initial reports of PI-based AMR treatment in refractory rejection demonstrated the ability of bortezomib to deplete plasma cells producing DSA, reduce DSA levels, provide histological improvement or resolution, and improve renal allograft function. These results have subsequently been confirmed in a multicenter collaborative study. PI has also been shown to provide effective primary AMR therapy in case reports. Recent studies have demonstrated that PI therapy results in differential responses in early and late post-transplant AMR. Additional randomized studies are evaluating the role of PI in transplant induction, acute AMR, and chronic rejection in renal transplantation. An important theoretical advantage of PI-based regimens is derived from several potential strategies for achievement of synergy.
authors.affiliation: Department of Surgery, Division of Transplantation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0558, USA.
authors.forename: R Carlin
authors.initials: RC
authors.lastname: Walsh
authors.forename: Rita R
authors.initials: RR
authors.lastname: Alloway
authors.forename: Alin L
authors.initials: AL
authors.lastname: Girnita
authors.forename: E Steve
authors.initials: ES
authors.lastname: Woodle
mesh_terms: D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D016896:Treatment Outcome
chemical_list: D015853:Cysteine Proteinase Inhibitors; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex