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

TitleBrief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice.
Publication TypeJournal Article
Year of Publication2016
AuthorsKarreci ESula, Fan H, Uehara M, Mihali AB, Singh PK, Kurdi AT, Solhjou Z, Riella LV, Ghobrial I, Laragione T, Routray S, Assaker JPierre, Wang R, Sukenick G, Shi L, Barrat FJ, Nathan C, Lin G, Azzi J
JournalProc Natl Acad Sci U S A
Volume113
Issue52
PaginationE8425-E8432
Date Published2016 Dec 27
ISSN1091-6490
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.

DOI10.1073/pnas.1618548114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27956634
PubMed Central IDPMC5206568