title: Inhibition of the Immunoproteasome Subunit LMP7 with ONX 0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen-Disparate Murine Model.
abstract: In the current study we evaluated the effects of immunoproteasome inhibition using ONX 0914 (formerly PR-957) to ameliorate graft-versus-host disease (GVHD). ONX 0914, an LMP7-selective epoxyketone inhibitor of the immunoproteasome, has been shown to reduce cytokine production in activated monocytes and T cells and attenuate disease progression in mouse models of rheumatoid arthritis, colitis, systemic lupus erythematosus, and, more recently, encephalomyelitis. Inhibition of LMP7 with ONX 0914 in the B10.BR→CBA MHC-matched/minor histocompatibility antigen (miHA)-disparate murine blood and marrow transplant (BMT) model caused a modest but significant improvement in the survival of mice experiencing GVHD. Concomitant with these results, in vitro mixed lymphocyte cultures revealed that stimulator splenocytes, but not responder T cells, treated with ONX 0914 resulted in decreased IFN-γ production by allogeneic T cells in both MHC-disparate (B10.BR anti-B6) and miHA-mismatched (B10.BR anti-CBA) settings. In addition, a reduction in the expression of the MHC class I-restricted SIINFEKL peptide was observed in splenocytes from transgenic C57BL/6-Tg(CAG-OVA)916Jen/J mice exposed to ONX 0914. Taken together, these data support that LMP7 inhibition in the context of BMT modulates allogeneic responses by decreasing endogenous miHA presentation and that the consequential reduction in allogeneic stimulation and cytokine production reduces GVHD development.
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey. Electronic address: jzilberberg@hackensackum.org.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zilberberg
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Matos
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dziopa
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: Leah
authors.initials: L
authors.lastname: Dziopa
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Onyx Pharmaceuticals, South San Francisco, California.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Shahin
authors.initials: S
authors.lastname: Assefnia
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.
authors.forename: Robert
authors.initials: R
authors.lastname: Korngold
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; C542291:PR-957; D007371:Interferon-gamma; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: BMT; GVHD; Immunoproteasome; Murine models