Calcineurin Inhibitor Minimization With Ixazomib, an Investigational Proteasome Inhibitor, for the Prevention of Antibody Mediated Rejection in a Preclinical Model.
BACKGROUND
There is a need for new immunosuppression strategies to minimize calcineurin inhibitor (CNI) toxicity while effectively preventing antibody-mediated rejection (AMR).


METHODS
We tested the efficacy of an investigational proteasome inhibitor, ixazomib, alone and in a CNI minimization strategy in a rat kidney transplant model of transfusion-elicited acute AMR. Nonsensitized (naïve) and sensitized allograft recipients were randomized into 4 treatment groups (8 groups total, n = 3 to 6 in each group) and treated for 1 week. Groups included: no treatment, full dose cyclosporine (CsA, 10 mg/kg per day), ixazomib (0.25 mg/kg on days -5, -2 and +2) alone, and half dose CsA (5 mg/kg per day) + ixazomib.


RESULTS
Compared to untreated animals, ixazomib alone or in combination with ½ dose CsA reduced donor-specific antibody, intragraft transcripts for chemokines CCL-21 and CXCL-13, and CD19 expression in both sensitized and naïve transplants. Compared to full dose CsA, the CNI minimization strategy with ixazomib inhibited AMR and allograft injury as evidenced by reduced C4d staining in peritubular capillaries, microcirculation inflammation, splenic plasma cells, circulating B cell activating factor, and intragraft transcripts for major histocompatibility complex class II, Toll-like receptors (TLR-1, TLR-10, and TLR-12) and CCL-21 and CXCL-13 in sensitized animals, indicating downregulation of B cell activation, antigen presentation and T-cell and B-cell signaling.


CONCLUSIONS
These studies suggest that CNI minimization strategies including ixazomib are effective to prevent AMR including in sensitized kidney allograft recipients. Clinical studies are needed to determine the role of novel proteasome inhibitors for the prevention and treatment of AMR.
1 Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. 2 Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI. 3 Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health and Pathology and Laboratory Services, William S. Middleton Memorial Veterans Hospital, Madison, WI.
Shannon R
SR
Reese
Nancy A
NA
Wilson
Gengwen
G
Huang
Robert R
RR
Redfield
Weixiong
W
Zhong
Arjang
A
Djamali
D000208:Acute Disease; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology* / Q000633:toxicity; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D006084:Graft Rejection / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D056724:Immunity, Humoral / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007518:Isoantibodies / Q000097:blood*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D015415:Biomarkers; D001896:Boron Compounds; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D061988:Proteasome Inhibitors; C548400:ixazomib; D016572:Cyclosporine; D005998:Glycine