title: Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice.
abstract: Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c. DPLG3 suppressed cytokine release from blood mononuclear cells and the activation of DCs and T cells, diminished accumulation of effector T cells, promoted expression of exhaustion and coinhibitory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allografts across a major histocompatibility barrier. These findings demonstrate the potential value of using brief posttransplant immunoproteasome inhibition to entrain a long-term response favorable to allograft survival as part of an immunomodulatory regimen that is neither broadly immunosuppressive nor toxic.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Esilida
authors.initials: E
authors.lastname: Sula Karreci
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Hao
authors.initials: H
authors.lastname: Fan
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Uehara
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Albana B
authors.initials: AB
authors.lastname: Mihali
authors.affiliation: Department of Biochemistry, Milstein Chemistry Core Facility, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Kurdi
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Zhabiz
authors.initials: Z
authors.lastname: Solhjou
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
authors.forename: Irene
authors.initials: I
authors.lastname: Ghobrial
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021.
authors.forename: Teresina
authors.initials: T
authors.lastname: Laragione
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Sujit
authors.initials: S
authors.lastname: Routray
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Assaker
authors.affiliation: NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
authors.forename: George
authors.initials: G
authors.lastname: Sukenick
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021.
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; cnathan@med.cornell.edu gal2005@med.cornell.edu jazzi@rics.bwh.harvard.edu.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nathan
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065; cnathan@med.cornell.edu gal2005@med.cornell.edu jazzi@rics.bwh.harvard.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Lin
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; cnathan@med.cornell.edu gal2005@med.cornell.edu jazzi@rics.bwh.harvard.edu.
authors.forename: Jamil
authors.initials: J
authors.lastname: Azzi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006085:Graft Survival; D016027:Heart Transplantation / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: T-cell exhaustion; allograft; effector T cells; immunoproteasome; memory T cells