Proteasome inhibition for antibody-mediated allograft rejection.
Antibody-mediated rejection (AMR) is a major risk factor for graft loss following kidney transplantation. Traditional anti-humoral therapies provide suboptimal therapy and they do not deplete plasma cells, which are the source of antibody production. Proteasome inhibitors (PI) have been shown to deplete both transformed and nontransformed plasma cells in human transplant recipients and animal models; and therefore, offer a new paradigm for AMR, ie, plasma cell-targeted therapy. Bortezomib, a first in class proteasome inhibitor approved by the US Food and Drug Administration for treatment of multiple myeloma, has been used to treat AMR in several solid organ transplant recipients. The greatest experience with PI therapy for treating AMR is in kidney transplant recipients. Experiences to date with PI therapy have demonstrated that: (1) early AMR (within the first 6 months post-transplant) responds better than late AMR, and (2) the nature of the plasma cell clonal population influences sensitivity to PI therapy with plasma subsets greater than long-lived bone marrow niche-resident plasma cells. In conclusion, plasma cell-targeted therapy with PIs is a method for targeting plasma cells (the source of antibody production) with a well-elucidated mechanism of action and subsequent points of synergy, thereby providing an exciting new potential means for enhancing anti-humoral therapies.
Department of Internal Medicine, Division of Nephrology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Basma
B
Sadaka
Rita R
RR
Alloway
Adele R
AR
Shields
Nicole M
NM
Schmidt
E Steve
ES
Woodle
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D006084:Graft Rejection / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D010950:Plasma Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D000906:Antibodies; D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex