2. Academic Validation
  3. Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

  • Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8425-E8432. doi: 10.1073/pnas.1618548114.
Esilida Sula Karreci 1,  Hao Fan 2,  Mayuko Uehara 1,  Albana B Mihali 1,  Pradeep K Singh 3,  Ahmed T Kurdi 4,  Zhabiz Solhjou 1,  Leonardo V Riella 1,  Irene Ghobrial 4,  Teresina Laragione 5,  Sujit Routray 1,  Jean Pierre Assaker 1,  Rong Wang 6,  George Sukenick 6,  Lei Shi 7,  Franck J Barrat 5,  Carl F Nathan 8,  Gang Lin 8,  Jamil Azzi 9
Affiliations

Affiliations

  • 1 Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • 2 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065.
  • 3 Department of Biochemistry, Milstein Chemistry Core Facility, Weill Cornell Medicine, New York, NY 10065.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
  • 5 Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021.
  • 6 NMR Analytical Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
  • 7 Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065.
  • 8 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.
  • 9 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.
PMID: 27956634 DOI: 10.1073/pnas.1618548114
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.

Keywords

T-cell exhaustion; allograft; effector T cells; immunoproteasome; memory T cells.

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