文章基本信息

标题：Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice
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作者：Esilida Sula Karreci ; Hao Fan ; Mayuko Uehara 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：52
页码：E8425-E8432
DOI：10.1073/pnas.1618548114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe potential of proteasome inhibitors to prevent transplant rejection and to treat other immune disorders is hindered by mechanism-based toxicity from inhibition of constitutive proteasomes. Here, we demonstrate that briefly, reversibly, and selectively inhibiting the immunoproteasome prolonged the survival of transplanted hearts in mice and allowed long-term survival when combined with single-dose CTLA4-Ig. Immunoproteasome inhibition noncytotoxically reduced T-cell proliferation and the numbers of effector T cells in the allograft and draining nodes while increasing T-cell expression of exhaustion markers. The immunoproteasome thus appears to play a role in suppressing induction of T-cell exhaustion. Selective inhibition of the immunoproteasome may be a potential treatment option for the management of transplant rejection. 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 {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.
关键词：allograft ; effector T cells ; immunoproteasome ; memory T cells ; T-cell exhaustion