Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion

There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibito...

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Bibliographic Details
Published in:Experimental hematology 2017-04, Vol.48, p.50-57
Main Authors: Al-Homsi, Ahmad Samer, Goodyke, Austin, Cole, Kelli, Muilenburg, Marlee, McLane, Michael, Abdel-Mageed, Sarah, Feng, Yuxin
Format: Article
Language:English
Subjects:
Advanced Basic Science
Animals
Boron Compounds - pharmacology
Cell Differentiation - drug effects
Cell Differentiation - immunology
Cytokines - metabolism
Dendritic Cells - cytology
Dendritic Cells - drug effects
Dendritic Cells - immunology
Dendritic Cells - metabolism
Disease Models, Animal
Female
Glycine - analogs & derivatives
Glycine - pharmacology
Graft vs Host Disease - drug therapy
Graft vs Host Disease - etiology
Hematology, Oncology and Palliative Medicine
Hematopoietic Stem Cell Transplantation - adverse effects
Humans
Immunomodulation - drug effects
Mice
Protease Inhibitors - pharmacology
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Transplantation, Homologous
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Summary:There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. We also determined the effects of ixazomib in a murine GvHD model. Although ixazomib suppressed naïve human DC maturation, it had only a limited effect on cell viability. Ixazomib decreased pro-inflammatory cytokine production of resting DCs. This effect was diminished or reversed when DCs were pre-stimulated. In vivo, ixazomib administered post-transplantation on days +1 and +4 or days −1, +2, and +5 ameliorated GvHD in comparison to the GvHD group. Although a fraction of mice treated according to the prolonged schedule died abruptly after the day +5 treatment, both schedules resulted in improved overall survival. When we examined the effects of ixazomib on splenic cells and serum cytokines, we found that ixazomib exerted complex schedule-dependent immunomodulatory effects. Our study provides a rationale for the potential use of ixazomib in the prevention of GvHD.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2016.12.002