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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 ?5i that has thousands-fold selectivity over constitutive ?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.

SUBMITTER: Sula Karreci E 

PROVIDER: S-EPMC5206568 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Sula Karreci Esilida E   Fan Hao H   Uehara Mayuko M   Mihali Albana B AB   Singh Pradeep K PK   Kurdi Ahmed T AT   Solhjou Zhabiz Z   Riella Leonardo V LV   Ghobrial Irene I   Laragione Teresina T   Routray Sujit S   Assaker Jean Pierre JP   Wang Rong R   Sukenick George G   Shi Lei L   Barrat Franck J FJ   Nathan Carl F CF   Lin Gang G   Azzi Jamil J  

Proceedings of the National Academy of Sciences of the United States of America 20161212 52


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 immunoproteaso  ...[more]

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