Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice Journal Article
| Authors: | Karreci, E. S.; Fan, H.; Uehara, M.; Mihali, A. B.; Singh, P. K.; Kurdi, A. T.; Solhjou, Z.; Riella, L. V.; Ghobrial, I.; Laragione, T.; Routray, S.; Assaker, J. P.; Wang, R.; Sukenick, G.; Shi, L.; Barrat, F. J.; Nathan, C. F.; Lin, G.; Azzi, J. |
| Article 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. |
| Keywords: | allograft; effector t cells; immunoproteasome; memory t cells; t-cell exhaustion |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 113 |
| Issue: | 52 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2016-12-27 |
| Start Page: | E8425 |
| End Page: | E8432 |
| Language: | English |
| DOI: | 10.1073/pnas.1618548114 |
| PROVIDER: | scopus |
| PMCID: | PMC5206568 |
| PUBMED: | 27956634 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 February 2017 -- Source: Scopus |
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