Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 52, Pages E8425-E8432Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1618548114
Keywords
allograft; effector T cells; immunoproteasome; memory T cells; T-cell exhaustion
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Funding
- American Heart Association grant
- Milstein Program in Translational Medicine and Chemical Biology
- Alliance for Lupus Research
- Daedalus Fund for Innovation at Weill Cornell Medicine
- William Randolph Hearst Trust
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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 auto-immunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit beta 5i that has thousands-fold selectivity over constitutive beta 5c. 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.
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