title: Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashion.
abstract: 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.
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI; Michigan State University College of Human Medicine, Grand Rapids, MI. Electronic address: A.Samer.Al-Homsi@SpectrumHealth.org.
authors.forename: Ahmad Samer
authors.initials: AS
authors.lastname: Al-Homsi
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
authors.forename: Austin
authors.initials: A
authors.lastname: Goodyke
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
authors.forename: Kelli
authors.initials: K
authors.lastname: Cole
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
authors.forename: Marlee
authors.initials: M
authors.lastname: Muilenburg
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
authors.forename: Michael
authors.initials: M
authors.lastname: McLane
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abdel-Mageed
authors.affiliation: Adult Blood and Marrow Transplantation, Spectrum Health, Grand Rapids, MI.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000209:etiology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D001896:Boron Compounds; D016207:Cytokines; D011480:Protease Inhibitors; C548400:ixazomib; D005998:Glycine