Calcineurin Inhibitor Minimization With Ixazomib, an Investigational Proteasome Inhibitor, for the Prevention of Antibody Mediated Rejection in a Preclinical Model

• Published in: Transplantation Vol. 99; no. 9; p. 1785
• Main Authors: Reese, Shannon R, Wilson, Nancy A, Huang, Gengwen, Redfield, 3rd, Robert R, Zhong, Weixiong, Djamali, Arjang
• Format: Journal Article
• Language: English
• Published: United States 01.09.2015
• Subjects: Acute Disease; Animals; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Biomarkers - blood; Biomarkers - metabolism; Boron Compounds - pharmacology; Boron Compounds - toxicity; Calcineurin Inhibitors - administration & dosage; Calcineurin Inhibitors - pharmacology; Calcineurin Inhibitors - toxicity; Cyclosporine - administration & dosage; Cyclosporine - pharmacology; Cyclosporine - toxicity; Disease Models, Animal; Drug Therapy, Combination; Gene Expression Regulation; Glycine - analogs & derivatives; Glycine - pharmacology; Glycine - toxicity; Graft Rejection - blood; Graft Rejection - enzymology; Graft Rejection - genetics; Graft Rejection - immunology; Graft Rejection - pathology; Graft Rejection - prevention & control; Graft Survival - drug effects; Immunity, Humoral - drug effects; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - toxicity; Isoantibodies - blood; Kidney - drug effects; Kidney - enzymology; Kidney - immunology; Kidney - pathology; Kidney Transplantation - adverse effects; Male; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - toxicity; Rats, Inbred BN; Rats, Inbred Lew; Signal Transduction - drug effects; T-Lymphocytes - drug effects; T-Lymphocytes - immunology
• ISSN: 1534-6080
• DOI: 10.1097/TP.0000000000000736

There is a need for new immunosuppression strategies to minimize calcineurin inhibitor (CNI) toxicity while effectively preventing antibody-mediated rejection (AMR). 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. 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. 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.